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Maurina et al. Mini-invasive Surg 2021;5:53 https://dx.doi.org/10.20517/2574-1225.2021.88 Page 9 of 13

Second, one of the main gaps in evidence is that no trial randomizing patients to either LAAO or OAC
exists. Therefore, LAAO does not have a Class I recommendation in current guidelines. The ASAP-TOO
trial, randomizing patients unsuitable for OAC to receive either LAAO or APT, was interrupted for poor
enrollment. This reflects the fact that LAAO is nowadays so popular and appears to be so safe that no
clinician wants to risk randomization to the APT arm. Hence, registries are fundamental and represent the
main source of data regarding LAAO procedures and different occlusion devices.

Then, additional evidence is needed to assess the safety and efficacy of LAA closure devices with respect to
DOACs. In fact, DOACs proved to be at least as safe and effective as warfarin in preventing stroke in non-
valvular AF and are now widely used in this subset of patients. Initial data came from observational studies.
[43]
Godino et al. showed comparable safety and efficacy between LAAO and DOACs in terms of
thromboembolic and major bleeding events in patients with non-valvular AF at high bleeding risk, whereas
another study found lower bleeding and mortality in LAAO rather than in DOAC patients . A first, non-
[3]
inferiority RCT showed that LAAO was non-inferior to DOAC in preventing both ischemic and
hemorrhagic complications in a high-risk cohort of AF patients , but more robust data from larger studies
[44]
are expected. The CLOSURE-AF (NCT03463317) is a prospective, RCT assessing the non-inferiority, and
possibly superiority, of percutaneous closure of the LAA with respect to both ischemic and bleeding risk in
high-risk patients vs. OAC (both DOACs and VKAs). It is going to be the largest trial ever conducted on
this topic. Data are expected to be available in 2023.

Another debatable aspect is the type and duration of antithrombotic therapy after LAAO. The SAFE-LAAC
(NCT03445949) trial is currently recruiting patients to evaluate the safety and efficacy of stopping DAPT
after 30 days rather than at 6 months. Investigators are also going to evaluate potential differences in
stopping all antithrombotic and antiplatelet agents six months after LAA occlusion vs. long-term treatment
with single antiplatelet agent. The ANDES trial (NCT03568890) is also currently recruiting patients to
compare DOAC vs. antiplatelet therapy for 8 weeks after percutaneous LAAO, for the prevention of DRT.
Promising results about the efficacy of lower dose DOACs came from the phase IIb ADRIFT trial, showing
lower thrombin generation after LAAO using rivaroxaban 10-15 mg daily rather than DAPT , but new,
[45]
larger trials are needed. The use of DOACs instead of antiplatelet agents in post-procedural antithrombotic
therapy may seem counterintuitive: however, the lower bleeding risk of DOAC with respect to warfarin and
the possibility of using reduced dosages might suggest a new role for anticoagulation in these patients.
Moreover, in the light of the recent evidence coming from the LAAOS III trial , LAAO could be
[30]
considered an adjunctive therapy to anticoagulation to reduce ischemic risk, despite striking differences
between surgical and percutaneous LAAO.

Other trials aim to perform head-to-head comparisons between LAAO devices analyzing safety, efficacy,
and specific indications for different devices. The largest ongoing trial is the Amulet IDE trial which
compares the Amplatzer device vs. the WATCHMAN™ device and whose initial results have recently been
[15]
published . In total, 1878 participants have been enrolled worldwide and will be followed for 5 years after
device implant, evaluating both stroke and bleeding risk, procedure-related complications, mortality, and
device closure. The most relevant ongoing trials are summarized in Table 2.

Moreover, no definitive consensus on the appropriate echocardiographic follow-up to assess device success
and complications has been published: whether a standardized approach might be useful in adapting
current clinical practice still has to be determined.