Antithrombotic Therapy After Left Atrial Appendage Occlusion: Double Antiplatelet Therapy vs Apixaban

The non-valvular atrial fibrillation (NVAF) is the most common rhythm disturbance in our midst. Its incidence is correlated with age; therefore a significant increase is expected in the coming years due to the progressive aging of the population. Moreover, NVAF is responsible for up to 20% of all ischemic strokes and implies a worse prognosis compared with stroke due to other etiologies1 Oral anticoagulation is the standard therapy on patients with NVAF to reduce embolic events. The new anticoagulant drugs (NOAC) including the direct thrombin inhibitors (dabigatran2) and Xa inhibitors (apixaban3 and rivaroxaban4) have revealed a more stable and secure profile comparing to vitamin K antagonist. However, these new molecules still have an increased risk of bleeding (annual rate of major and minor bleeding of 2.15 -3.6% and 15-20% respectively) that might limit the use in a large amount of patients. Indeed about 40% of patients with indication for OAC not receive despite the introduction of NOAC5.

Percutaneous closure of the left atrial appendage (LAA) is recommended by the guidelines for patients with NVAF and contraindication for oral anticoagulation6,7 The aim of the intervention is: first reducing strokes caused by thrombus originated in the LAA)and second suppression of antithrombotic therapy avoiding the risk of bleeding associated with use of these drugs.

There are two devices that have been used for LAA closure worldwide: the WatchmanTM system (Boston Scientific, Boston, Massachusetts, USA) and AmplatzerTM Cardiac Plug (ACP) (St. Jude Medical, Minneapolis, Minnesota, USA). The currently available data comes mainly from the only two existing randomized trials to date (PROTECT AF8 and PREVAIL9). In these two RCT, patients treated with the Watchman device showed not to be inferior in terms of mortality and thromboembolic events compared to those patients treated with oral anticoagulation. In these trials, patients eligible to oral anticoagulation and percutaneous LAA occlusion (LAAO) were included, an uncommon situation in routine clinical practice. Moreover, even those randomized to LAA closure were treated with warfarin for at least six weeks, making it difficult to assess the benefit of appendage closure in early stages..

The ACP is a self-expanding device specifically designed to completely cover the ostium of the appendage. It comprises a nitinol lobe and a disk connected by a central waist. There are no randomized controlled trials with this device, but there is a large experience in registries including mainly patients with formal contraindication to OAC10,11 Despite the growing evidence about this technique, there are several questions that need to be answered: 1) Device thrombosis is a rare complication, but it has been described with the both devices (Watchman and ACP) 10-13. The incidence of device thrombosis is ranging between 2 and 17%, this wide variation might be due to misdiagnosis in some series since the incidence is higher in those series were more TEE were performed13,14. The relevance of device thrombosis is unclear; some series have showed a lack of correlation between the presence of device thrombosis and stroke (i0.3% of thrombosis have clinical translation) 12-14, but the experience its limited and device thrombosis and stroke remain as one of the most feared complications. 2) The presence of peri-device leaks during follow-up still has an uncertain meaning and makes difficult the decision of stopping antithrombotic therapy. In the surgical experience with appendage excision during mitral valve surgery, it was observed that incomplete excision of the OI was associated with a higher rate of embolic events. However, LAA percutaneous occlusion (LAAO) publications have not showed a clear relation between the presence of leaks and clinical events (stroke or device thrombosis)14,15. 3) Another point of controversy lies in the antithrombotic recommendations following the procedure. Since most of device thrombosis occur during the first trimester after closure and have been successfully treated with heparin or LWMH, the use of oral anticoagulation during the initial phase has been postulated 8,9. However, most of the patients treated with LAAO have a high risk of bleeding, and since the incidence and embolic potential of device thrombosis remains unclear, it makes difficult to justify the use of anticoagulation on this patients. In the other hand, dual antiplatelet therapy (DAT) has been used based on the prior experience with coronary stents. However, despite revealing a low device thrombosis and stroke rate, this protocol has not shown a reduction on major bleeding12,14-16.

In summary, the best antithrombotic therapy after LAA closure needs to provide a balance between efficacy (for prevention of thrombosis device) and safety (for the occurrence of major bleeding). Mainly because patients treated with therapy show a high risk for thromboembolic events (CHADS high) and concomitantly, a high incidence of haemorrhagic events (high HASBLED). According to data from large LAA closure registries14,16 the main indications for appendage closure are gastrointestinal and intracranial bleeding, therefore patients with absolute or relative contraindication for OAC. The rate of intracranial or gastrointestinal bleeding with DAT is up to 7%, being even higher than OAC 17,18. With the aim of reducing the risk of bleeding, LAA closure protocols have tried to reduce the DAT to 3 months, but with no solid evidence. Meanwhile, the introduction of NOAC has opened a new spectrum of therapeutic options. Among this new generation of antithrombotic molecules Apixaban has shown a really good safety and efficacy profile with low rate of ischemic and haemorrhagic events3. Moreover, Apixaban has already been use to treat LAA and device thrombosis with success19. In this regard, we believe that Apixaban would improve the rates of efficacy (reducing device thrombosis) and safety (with lower rate of bleeding) compared to DAT after LAA percutaneous closure. In fact, antithrombotic therapy post-LAAO is not given to treat any thrombus; it is given just to prevent its formation. In this sense, both 2.5 mg and 5 mg/12h of Apixaban have shown in terms of deep vein thrombosis (DVT) prevention20 and even the low dose of Apixaban has been shown effective to treat LAA thrombus21 . Since some patients undergoing LAAO present an extremely fragile profile and many patients have bled with different OAC strategies, including NOACs, we propose a strategy of 2.5 or 5 mg/12h of Apixaban based on the expected bleeding risk as this would provide the best balance between efficacy in preventing thrombus formation and avoid any kind of bleeding during the first 3 months after LAAO.