The Fourth Left Atrial Appendage Occlusion Study: (LAAOS-4)

Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia and
is associated with a 3-5-fold increased risk of ischemic stroke. AF is when the
top two chambers of the heart, the atria, beat too fast and with an irregular
rhythm (fibrillation). While AF is associated with several mechanisms of
ischemic stroke, most strokes in patients with AF are due to cardio-embolism.
This is when as a result of the heart*s reduced pumping efficiency, clots form
in the left atrial appendage (LAA) and are pumped out into the circulatory
system where they may block an artery resulting in a systemic embolism or may
block the blood supply to the brain causing a stroke. Strokes attributable to
AF frequently cause damage to large areas of brain tissue, frequently resulting
in severe disability or death.

In patients with AF, long-term oral anticoagulation with a vitamin K antagonist
(VKA) substantially reduces the risk of ischemic stroke compared to placebo
(relative risk reduction 67%, 95% confidence interval 54% to 77%), but
increases the risk of major bleeding. The direct oral anticoagulants (DOACs)
targeted at single components of the coagulation cascade are as effective as
VKAs for ischemic stroke prevention. In addition, in four pivotal clinical
trials, these drugs consistently showed a lower risk for hemorrhagic stroke
compared to VKA treatment. Therefore, current North American and European
guidelines for the management of patients with AF strongly recommend long-term
oral anticoagulation for patients with risk factors for stroke; with a
preference for DOACs. Despite its effectiveness, there is still a risk of
ischemic stroke and those with an elevated CHA2DS2-VASc score have a higher
absolute residual risk of stroke despite OAC, which can exceed 2% per year.
This can be attributed to several limitations of OAC such as problems related
to dose selection, control of anticoagulation intensity, biological variability
in response, compliance and therapy interruptions. Thus, we can identify a
substantial group of patients who have a high stroke risk despite being on OAC,
especially those with a history of stroke or with CHA2DS2-VASc score of >= 4 who
would benefit from therapies which can be added to anticoagulation, and which
overcome its limitations.

Studies have also found that the risk of stroke can be reduced via left atrial
appendage occlusion (LAAO), either by closing off the left atrial appendage
surgically by cutting, over-sewing or clipping the LAA or catheter-based
closure either endovascularly or a hybrid endovascular/epicardial approach. The
rationale for doing such a procedure is that the environment where stasis
occurs and clots are formed is thereby eliminated. The permanence of LAAO as a
stroke prevention therapy specifically addresses the main limitation of OAC
therapy (namely that it is often stopped, either temporarily or permanently).
The recent LAAOS III study results now provide very strong evidence in support
of LAAO as an additional stroke prevention as a complement to OAC. LAAOS III
randomized patients with AF already receiving oral anticoagulation and who were
coming for cardiac surgery to undergo surgical LAAO (removal, stitch closure or
closure with a device) or not. Over mean follow up of 3.8 years, the risk of
ischemic stroke or systemic embolism was reduced by 33% compared with OAC only.
LAAO was not associated with any safety issues. Although surgical LAAO has now
been proven effective as an addition to OAC therapy, only patients who undergo
open cardiac surgery for other reasons can benefit. It is not known if a
similar benefit would occur if patients with AF on OAC were to receive LAAO
using an endovascular device such as the WATCHMAN device. However, given the
substantial benefit of LAAO observed in the LAAOS III trial and the large
number of AF patients with significant residual stroke risk, additional trials
are needed to determine if stand-alone, catheter-based occlusion of the LAA can
prevent ischemic stroke and systemic embolism in patients with atrial
fibrillation who remain at high risk of stroke despite being on OAC therapy.
(protocol section 2. Introduction, 2.1 background, page 8-9)

To determine if catheter-based endovascular left atrial appendage occlusion
(LAAO) prevents ischemic stroke or systemic embolism in participants with
atrial fibrillation (AF), who remain at high risk of stroke, despite receiving
ongoing treatment with oral anticoagulation.

Multicentre, prospective, open-label, randomized controlled trial with blinded
assessment of endpoints (PROBE).

N/A

N/A