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E-mail:j-goldberger@miami.edu
Sarris-Michopoulos et al. reviewed the role of the left atrial appendage
(LAA) in atrial fibrillation (AF) related stroke and current techniques
for targeting it for stroke
reduction.1The authors propose that further trials to assess LAA exclusion as an
alternative to anticoagulation for patients with AF should strongly be
considered. Any such consideration should take into account the
potential risks and benefits, and ultimately be supported by randomized
clinical trial data. The latter is lacking at the present time, so we
will consider the potential risks and benefits.
The LAA is often considered to be a vestigial portion of the left
atrium; however, it does have a physiologic role in humans. The LAA is a
remnant of the embryonic left atrium that develops during the third week
of fetal
life.2 It
has several functions that continue into adulthood including serving as
a reservoir during left ventricular systole, a conduit for blood from
the pulmonary veins into the left ventricle during diastole, a chamber
to augment left ventricular filling in late diastole, and a filling
chamber for volume
reserve.2Furthermore, the LAA plays an important endocrine role. It contains
stretch receptors to excrete atrial natriuretic peptide in response to
changes in left atrial pressure to increase
natriuresis.2Removal of the LAA eliminates these functional roles. Interestingly, it
has been shown that patients undergoing LAA exclusion have elevated left
atrial
pressure.3
It has been established that patients with AF undergoing cardiac surgery
for another indication benefit from LAA occlusion at the time of
surgery. In the LAAOS III (Left Atrial Appendage Occlusion during
Cardiac Surgery to Prevent Stroke) multicenter trial, 4,811 participants
with a mean CHA2DS2-VASc score of 4.2
were randomized to undergo either LAA occlusion or no occlusion. The
patients were followed for a mean of 3.8 years. Stroke or systemic
embolism occurred in 114 participants (4.8%) in the occlusion group and
168 (7.0%) in the no-occlusion group (HR 0.67, 95% CI: 0.53-0.85, p =
0.001).4Of note, 76.8% of patients remained on oral anticoagulation at 3 years,
supporting the role of LAA occlusion as an adjunct to and not a
replacement for anticoagulation.
The concept of LAA occlusion/ligation as an alternative to
anticoagulation is considered based on the data that approximately 90%
of non-rheumatic atrial fibrillation left atrial thrombi can be
localized to the
LAA.5 If
correct, this implies that about 10% of left atrial thrombi in patients
with atrial fibrillation would not be addressed by LAA occlusion. If
anticoagulation is not contraindicated, there would therefore
theoretically still be benefit for anticoagulation to address these
non-LAA thrombi. Future clinical trials to assess the additional benefit
for anticoagulation in patients who have undergone LAA
occlusion/ligation would be important to address this question but will
be challenging due to the noninferiority design that would be required
and the low event rate.
Available data from trials comparing LAA closure to warfarin have
provided some evidence of lower efficacy for LAA closure in reducing
ischemic stroke. The most studied device, the endovascularly placed
Watchman, shows a trend towards reduced efficacy in preventing ischemic
stroke. The five-year outcomes of the PREVAIL (Evaluation of the
WATCHMAN LAA Closure Device in Patients with Atrial Fibrillation Versus
Long Term Warfarin Therapy) did not meet noninferiority for the first
composite coprimary endpoint of stroke, systemic embolism, or
cardiovascular/unexplained death. A meta-analysis of the PREVAIL and
PROTECT AF (WATCHMAN Left Atrial Appendage system for embolic Protection
in Patients with Atrial Fibrillation) trials did show a similar
composite endpoint of stroke, systemic embolism, or cardiovascular death
between groups (HR 0.82, 95% CI 0.58-1.17 p = 0.27). However, there was
a numerically higher rate of ischemic stroke in the Watchman group (HR
1.71, 95% CI 0.94-3.11, p = 0.08) but a lower rate of hemorrhagic
stroke (HR 0.20, 95% CI 0.07-0.56, p =
0.0022).6
It is debatable how to apply these data in the current age of
non-warfarin direct oral anticoagulant (DOAC) use. Compared to warfarin,
DOACs have a lower risk of both stroke/systemic embolism (HR 0.81, 95%
CI 0.74-0.89) and intracranial bleeding (HR 0.45, 95% CI
0.37-0.56).7The PRAGUE-17 (Left Atrial Appendage closure versus Novel
Anticoagulation Agents in Atrial Fibrillation) trial compared Watchman
closure with DOACs. Closure with the Watchman device met non-inferiority
for the composite endpoint of cardiovascular death, all-stroke/transient
ischemic attack, clinically relevant bleeding, and
device/procedure-related complications) (sHR = 0.81, 0.56-1.18, p=0.27,
p-value for noninferiority = 0.006). There was a numerical but not
statistically significant increase in the all-stroke rate (HR 1.38,
0.63-3.03, p
=0.42).8
It is unclear how the data from Watchman would extend to surgical LAA
occlusion. While these surgical techniques appear promising, the data
presented in the review article by Sarris-Michopoulos et al. is entirely
from observational
studies.1The total number of subjects in these studies is 442
patients.9–11This is less than aforementioned randomized Watchman trials which
enrolled 707 patients in the PROTECT AF, 407 patients in PREVAIL, and
402 patients in PRAGUE-17. Even these studies enrolled many fewer
patients than the seminal trials of DOACs versus warfarin: 18,133 in
RE-LY (Randomized Evaluation of Long-Term Anticoagulation
Therapy)12,
14,264 in ROCKET-AF (Rivoxaraban Once Daily Oral Direct Factor XA
Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke
and Embolism Trial in Atrial
Fibrillation)13,
18,201 patients in ARISTOTLE (Apixaban for Reduction in Stroke and Other
Thromboembolic Events in Atrial
Fibrillation)14,
and 21,105 patients in ENGAGE AF-TIMI 48 (The Effective Anticoagulation
with a Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in
Myocardial Infarction 48)15 for a
total of 71,703 patients. It is therefore difficult to make conclusions
regarding the safety and efficacy of these LAA occlusion techniques.
Furthermore, we must be careful not to extend the findings of one LAA
occlusion method to another.
We agree with Sarris-Michopoulos et al. that this is an exciting field
that needs further randomized trials. The technology behind nonsurgical
LAA occlusion techniques such as Watchman, Amplatzer Amulet, and Lariat
will likely continue to evolve. There is good reason to hope that new
iterations of these devices will have less complication rates but
whether they can become the primary approach to prevent ischemic strokes
is unknown. For example, the Watchman FLX device has an improved design
to increase safety and efficacy. We look forward to the results of the
CHAMPION-AF study that will randomize patients to Watchman FLX versus
DOAC
treatment.16Similar efforts are needed to provide evidence from randomized
controlled trials for surgical techniques such as LAA clipping. While
the therapeutic landscape is being investigated, it is also important to
point out that there is tremendous opportunity to refine our diagnostic
approach to stroke prevention in patients with AF. The current standard
assessment – the CHA2DS2-VASc score –
has only a mediocre C-statistic estimated to range from
0.61-0.68.17,18The cumulative one year risk for thromboembolic events in patients with
atrial fibrillation with CHA2DS2-VASc
scores ≥ 2 (accounting for 89% of the AF patients) who are not
anticoagulated is estimated at
4.5%.19This indicates that the majority of patients with atrial fibrillation do
not experience stroke but are subjected to the risks of anticoagulation.
Better diagnostic approaches to identify which patients are at risk and
which are not could have tremendous public health ramifications. There
is active current interest in defining the atrial myopathy or
cardiopathy that is associated with
stroke.20–22Several techniques have been under investigation, including LAA
size/morphology,23,24electrocardiogram P wave
morphology,25,26echocardiographic LA
strain,27,28epicardial adipose
tissue,29troponin and N terminal pro-brain natriuretic peptide
levels30,31,
and 4D flow MRI to evaluate left atrial and LAA
stasis.32–34There is also ongoing research into “pill-in-pocket” anticoagulation
that would use continuous smartwatch monitoring to target
anticoagulation to intermediate risk patients during high risk time
periods.35Combined efforts in the diagnostic and therapeutic realm are most likely
to achieve improved clinical results for stroke prevention in atrial
fibrillation.