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\begin{document}

\title{Delayed pericardial effusion after left atrial appendage closure with
the LAmbre device: importance of a fully open umbrella}



\author[1]{Fangyi Xiao}%
\author[2]{yanyan chen}%
\author[3]{yi he chen}%
\author[4]{Xiaodong Zhou}%
\author[4]{Xinlei Wu}%
\author[4]{xiao chen}%
\author[5]{Liangguo Wang}%
\author[2]{Ying Fang}%
\author[4]{Lan Su}%
\author[6]{weijian huang}%
\affil[1]{the First Affiliated Hospital of Wenzhou Medical University ZheJiang 325000 P.R. China  }%
\affil[2]{The First Afﬁliated Hospital of Wenzhou Medical University}%
\affil[3]{the second afﬁliated hospital of Wenzhou Medical University}%
\affil[4]{The First Affiliated Hospital of Wenzhou Medical University}%
\affil[5]{he First Affiliated Hospital of Wenzhou Medical University}%
\affil[6]{The First Affiliated Hospital of Wenzhou Medical College}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Introduction: We aimed to investigate whether a modified implantation
method facilitating a fully open umbrella can reduce the pericardial
effusion/pericardial tamponade (PE/PT) rate after left atrial appendage
closure (LAAC) with the LAmbre device compared with the conventional
method (CM) in patients with non-valvular atrial fibrillation (NVAF).
Methods and results: Patients with NVAF who received either isolated
LAAC or combined catheter ablation and LAAC using the LAmbre device at
the First Affiliated Hospital of Wenzhou Medical University from January
2018 to December 2019 were enrolled. CM was used for device implantation
in the initial 59 patients, while a modified method (MM) was used in the
remaining 165 patients. Successful implantation was achieved in 98.3\%
of patients in the CM group and in 98.8\% in the MM group. A higher rate
of a fully open umbrella (98.8\% vs 69\%, P\textless{}0.001), less
requirement for recapture (46\% vs 62.1\%, P=0.036), and a lower
incidence of delayed PE/PT (1.2\% vs 8.6\%, P=0.005) were found in the
MM group compared with in the CM group. All of the five delayed PT
events occurred in patients with combined treatment. An umbrella that
was not fully open was the only factor associated with delayed PE/PT
events in a multivariable Cox model. Conclusions: LAAC with the LAmbre
device using an MM significantly increases the rate of a fully open
umbrella and decreases the requirement for recapture and the incidence
of delayed PE/PT. This method is more effective in patients with
combined treatment.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Transcatheter left atrial appendage closure (LAAC) has emerged as a
reasonable alternative to long-term oral anticoagulant therapy (OAT) for
stroke prevention in patients with non-valvular atrial fibrillation
(NVAF). Randomized trials for the Watchman
device\textsuperscript{1-3}and large, all-comer registries for Amplatzer
devices\textsuperscript{4,5} have shown promising clinical outcomes in
preventing stroke and avoiding bleeding events. Additionally, combined
catheter ablation, including radiofrequency ablation and cryoablation
with LAAC using Watchman or Amplatzer devices in a single procedure,
were reported to be effective and safe strategies in patients who had
indications for atrial fibrillation (AF) ablation and
LAAC\textsuperscript{6-9}.

The LAmbre\textsuperscript{TM} occluder was recently introduced to
clinical practice and small registry studies have shown high success
rates for implantation and acceptable periprocedural complication
rates\textsuperscript{10-12}. Data of a combined procedure with the
LAmbre device are still lacking. Different to Amplatzer devices, the
umbrella of the LAmbre device has a double stabilization design with
eight small distal hooks that engage into the wall of the left atrial
appendage (LAA) and eight U-shaped ends trapping in LAA trabeculations
(Figure 1). Previous studies\textsuperscript{11,13} showed that delayed
cardiac effusion/cardiac tamponade (PE/PT) events might occur following
LAAC with the LAmbre device.

We retrospectively investigated the safety and short-term outcome in
patients who underwent isolated LAAC with the LAmbre device or combined
treatment of catheter ablation for AF and LAAC. A modified method (MM)
for LAmbre device implantation was compared with the conventional method
(CM) in this study.

\textbf{Study population}

Patients with NVAF at a high risk of stroke who underwent LAmbre
implants (Lifetech Scientific Corp., Shenzhen, China) at The First
Affiliated Hospital of Wenzhou Medical University from January 2018 to
December 2019 were included. The inclusion criteria for LAAC were as
follows: age \textgreater{}18 years,
CHA\textsubscript{2}DS\textsubscript{2}-VASc score [?]2, contraindication
to long-term OAT, patients with bleeding events with or without
anticoagulation therapy, stroke despite OAT, and intolerance or refusal
to take OAT. The exclusion criteria were as follows: comorbid unstable
angina or acute myocardial infarction, a left atrial inner diameter
\textgreater{}65 mm, valvular heart disease, left atrial thrombus, a
history of LAA ligation, a history of inferior vena cava filter
placement surgery, severe infection, tumours, other diseases requiring
systemic anticoagulation, new onset stroke events within 1 month, active
bleeding disease, and a left ejection fraction [?]30\%. The conventional
implantation method was used in the LAAC procedure in the initial 59
patients (CM group) and an MM was used in the subsequent 165 patients
(MM group). All patients received pre-procedural transesophageal
echocardiography (TEE) to assess anatomy of the LAA and to exclude
thrombus of the LAA. Written informed consent was obtained from all of
the participants. The study was approved by the ethics committee of the
local institution.

\textbf{LAA closure with the LAmbre device}

The LAAC procedure was performed under local anaesthesia. Transseptal
puncture was performed via right femoral venous access under
fluoroscopic guidance. The sizes of the landing zone and the orifice
were measured from LAA angiography at the right anterior oblique and
caudal projection. The appropriate LAmbre size was selected on the basis
of the intraoperative angiographic and preoperative TEE measurements.
The size of the implant was 4 to 8 mm larger than the measured LAA
orifice based on the clinical judgement of the operators. The CM was
described as previously reported\textsuperscript{14}. In brief, the
delivery sheath was placed in the proximal part of the LAA. The distal
umbrella was released into the LAA by stepwise pushing out of the device
from the delivery sheath. Subsequently, the sheath was withdrawn to
expose the proximal cover. The umbrella was adjusted to open as fully as
possible. In the MM, the distal umbrella was initially half deployed
outside of the LAA (defined as when a radio-opaque marker of the LAmbre
device was located between two distal marker bands at the end of the
delivery sheath and it was closer to the proximal marker band) and then
gently ``en-bloc'' advanced into the proximal part of the LAA. Complete
deployment of the umbrella to the landing zone was subsequently achieved
by pushing out the device from the delivery sheath (Figure 2). The
manipulation to expose the cover was the same as that for the CM. A
fully open umbrella was defined as when the nadir of the U-shaped hooks
was at the same level as the radio-opaque marker connecting the umbrella
and cover in fluoroscopic imaging (Figure 1B). Stability was confirmed
by the tug test. The position of the device and any presence of
peri-device leakage were assessed by fluoroscopy and two-dimensional TEE
(0\selectlanguage{ngerman}°, 45°, 90°, and 135°) and following three-dimensional TEE under local
laryngeal anaesthesia with tetracaine. Patients who could not tolerate a
TEE examination were sedated with etomidate and fentanyl. Recapture
and/or resizing of the device was attempted unless the device was in a
satisfactory position and no major peri-device leakage (leakage \selectlanguage{english}[?]3 mm)
was achieved. The activated clotting time was adjusted to maintain 250
to 350 s during the procedure.

\textbf{Radiofrequency ablation for AF}

In patients with the combined procedure, radiofrequency ablation was
performed before LAAC under conscious sedation, with fentanyl and
midazolam for pain relief. Following double transseptal punctures, a
left atrial (LA) anatomical map was created using a 10-pole spiral
catheter (Lasso NAV; Biosense Webster, Inc., Diamond Bar, CA) under the
guidance of a three-dimensional electroanatomical mapping system (CARTO
3; Biosense Webster, Inc.). A contact-force catheter (Thermocool
SmartTouch; Biosense Webster, Inc.) was used to perform ablation
index-guided circumferential pulmonary vein isolation with target values
(450 for the anterior wall and 350 for the posterior wall). The endpoint
of ablation was bidirectional conduction block between the left atrium
and pulmonary veins. In patients with persistent AF, cardioversions were
delivered to restore sinus rhythm after circumferential pulmonary vein
isolation. Substrate modification was then performed as previously
described\textsuperscript{15}.

\textbf{Post-procedural management and follow-up}

All patients received transthoracic echocardiography to rule out
pericardial effusion on the following day of procedures. OAT was
administrated for at least 45 days in patients with isolated LAAC and
for 2 months in patients with the combined procedure. This treatment was
followed by aspirin and clopidogrel for 6 months and aspirin or
clopidogrel for life. At 45 days, 6 months, and 12 months of follow-up,
TEE was performed to evaluate the position of the device, residual flow,
and thrombus formation on the surface of the device.

\textbf{Major adverse events}

Major adverse events were defined as death, stroke, systemic embolism,
device embolization, pericardial bleeding requiring an intervention
(pericardial tamponade), atrio-oesophageal fistula, pulmonary vein
stenosis, or other major bleeding requiring invasive treatment or blood
transfusion.

\textbf{Statistical analysis}

Quantitative data are expressed as mean +- standard deviation and were
compared using the two-tailed t test. Categorical data are expressed as
percentages and were compared using the chi-square test. Comparisons of
events by groups were made by Kaplan--Meier analysis and the log-rank
test. Predictors of delayed PE/PT were analysed by univariate and
subsequent multivariate Cox regression analyses. The results were
expressed as hazard ratios (HRs) with 95\% confidence intervals (CIs).
P\textless{}0.05 was considered statistically significant. All
statistical analyses were performed using SPSS version 23.0.

\textbf{Results}

\textbf{Baseline characteristics of the patients}

Table 1 showed the baseline demographic data of the patients. The mean
age of the patients was 71 years in the CM group and 70 years in the MM
group. The prevalence of paroxysmal atrial fibrillation (PAF) was 55.6\%
and 50.0\% in the CM and MM groups, respectively. The
CHA\textsubscript{2}DS\textsubscript{2}-VASc scores were similar in the
two groups. The mean HAS-BLED score was also similar in the two groups.
There were significantly more patients with the combined procedure
(67.9\% vs 45.8\%, P=0.003) and with prior stroke (65.5\% vs 50.8\%,
P=0.048) in the MM group than in the CM group.

\textbf{Procedural characteristics}

The LAAC procedure with the LAmbre device was successfully performed in
58 (98.3\%) patients in the CM group and in 163 (98.8\%) patients in the
MM group. There were no significant differences in LAA size and LAA
anatomy between the two groups. The mean umbrella and cover diameters of
the implanted device were similar in the two groups. The rate of a fully
open umbrella was significantly higher in the MM group than in the CM
group (P\textless{}0.001). The rate of a device requiring recapture and
the mean number of recaptures were significantly lower in the MM group
than in the CM group (both P\textless{}0.05). LAAC with complete
coverage of the LAA\textsuperscript{16} was achieved in most of the
patients in both groups (70.2\% vs 60.3\%). The rates of partial
prolapse and complete prolapse into the LAA neck were also similar in
the two groups (Table 2).

\textbf{Adverse events}

No severe intra-procedural complications, including PE/PT, device
embolization, air embolism, thromboembolism, and death, occurred in
either group. Delayed PE/PT developed in five patients in the CM group
and in two patients in the MM group (Table 3). Umbrellas that were not
fully open were found in all of the five patients with delayed PE/PT in
the CM group, while fully open umbrellas were found in the two patients
with delayed PE/PT in the MM group (Figure 3). In the CM group, moderate
PE was found by echocardiography in the 9\textsuperscript{th} patient
with persistent AF on day 15 who underwent isolated LAAC and in the
52\textsuperscript{nd} patient with paroxysmal AF who received combined
treatment 2 days after the procedure. Both of these patents were managed
conservatively without further complications. Delayed PT occurred in
three patients who received the combined procedure requiring
intervention in the CM group. Sero-haemorrhagic liquid (haemoglobin
value was close to that in blood) was drained in all of these patients.
The 31\textsuperscript{st} patient with PAF developed PT on day 8 after
the operation. She was successfully treated with pericardiocentesis with
no long-term sequelae. The 42\textsuperscript{nd} patient with
persistent AF developed PT on day 18 after the procedure and was treated
with pericardiocentesis. The 59\textsuperscript{th} patient with PAF
suffered from progressive dyspnoea from 8 h after the procedure in the
night and received pericardiocentesis 15 h after the procedure. Cardiac
arrest occurred in preparation of pericardiocentesis. The patient died 7
days after the procedure owing to multi-organ failure. In the MM group,
the 110\textsuperscript{th}patient with persistent AF who received the
combined procedure developed PT on day 51 after the procedure and was
successfully treated with pericardiocentesis. The
174\textsuperscript{th} patient with PAF who underwent the combined
procedure developed PT 30 min after the procedure. Pericardiocentesis
was performed immediately in this patient. Surgical management of PT was
required because blood continually flowed out through the pigtail
catheter. A small branch of the left circumflex artery was bleeding,
which was likely perforated by a small shoulder hook of the device, was
explored during surgery. Excision of the LAA and coronary artery suture
were performed. The patient was discharged in a good condition on day 20
after surgery.

The delayed PE/PT rate was significantly lower in the MM group than in
the CM group (8.6\% vs 1.2\%, log-rank P=0.005). An umbrella that was
not fully open was the only factor associated with delayed PE/PT events
in univariate analysis (HR: 0.038, 95\% CI: 0.007--0.194;
P\textless{}0.001) and in the multivariable Cox model (HR: 0.026, 95\%
CI 0.004--0.183; P\textless{}0.001) after adjusting for age, sex, type
of AF, type of procedure, HAS-BLED score, type of anticoagulants, mean
number of recaptures, device position, LAA anatomy, the umbrella
diameter divided by the land zone diameter (measured at RAO 30deg, CAU 20deg
projection) ratio and the cover diameter divided by the orifice diameter
(measured at RAO 30deg, CAU 20deg projection) ratio (Tables 4, 5).

The 68\textsuperscript{th} patient had an ischaemic stroke 2 days after
the procedure. Severe stenosis of the basilar artery was found as the
cause of the stroke event. The 114\textsuperscript{th} patient with the
combined procedure suffered from gastrointestinal bleeding 24 days after
the operation owing to an intestinal tumour. Minor complications
included a haematoma at the puncture site in one patient with isolated
LAAC in the CM group and in two patients with the combined procedure in
the MM group, and a pseudoaneurysm at the puncture site in one patient
with combined treatment in the MM group. No device embolization,
device-related thrombus, stroke, death, atrio-oesophageal fistula, or
pulmonary vein stenosis was observed during 3 months of follow-up.

\textbf{Short-term TEE follow-up}

The first TEE follow-up rates were similar in both groups (87.9\% vs
87.7\%, P=0.968). The complete seal rates in the CM and MM groups were
68.6\% and 65.0\%, respectively. Peri-device leakage \selectlanguage{english}[?]3 mm was observed
in the majority of patients during follow-up TEE examinations, except
for two patients who had peri-device leakage of 4 mm in the MM group
(Figure 4).

\textbf{Discussion}

To the best of our knowledge, this is the largest study of LAAC using
the LAmbre device. We found a relatively high incidence of delayed PE/PT
after LAAC with the LAmbre device using a conventional implantation
method, mainly in patients with combined treatment. The MM for
implantation of the LAmbre device significantly facilitated full opening
of the umbrella, reduced the requirement of the recapture manoeuver, and
decreased the incidence of PE/PT. In multivariate Cox regression
analysis, an umbrella that was not fully open was the only factor
independently associated with delayed PE/PT events.

PE/PT is a serious complication, which mostly occurs during LAAC, but
rarely occurs after this procedure\textsuperscript{17}. Schmidt et
al\textsuperscript{18} found that the PE/PT rate was significantly
higher in patients who were implanted with the Watchman device in the
EWOLUTION study during sinus rhythm than in AF rhythm (0.2\% vs 1.5\%;
P=0.02) at day 30 post-implantation. Delayed PT events that required
intervention only occurred in LAAC during sinus rhythm. The
investigators speculated that the main mechanism for their finding was
LAA contraction during sinus rhythm exerting mechanical force on the
device, which eventually led to PE/PT. Wolfrum et
al\textsuperscript{19}compared the efficacy and safety of LAAC with the
Amplatzer Cardiac Plug according to the different position of the device
disc. No evidence for a difference in the occurrence PE/PT was found
between patients with complete versus incomplete Amplatzer Cardiac Plug
disc coverage of the LAA ostium. In contrast, a recent
study\textsuperscript{16} on the Amulet device reported a tendency
toward more PE/PT events after LAAC with incomplete coverage of the LAA
ostium by the proximal Amulet disc (P=0.07). This previous study
suggested that suboptimal positioning of the device might be associated
with worse periprocedural outcomes independent of repositioning or
exchange of the device during the procedure. In our study, delayed PE/PT
events were neither associated with the coverage position nor recapture
operation as analysed by univariate and subsequent multivariate Cox
regression analyses.

Huang et al\textsuperscript{10} reported encouraging clinical outcomes
in patients with NVAF who had implantation of the LAmbre LAA occluder.
Three PT events (timing of the events was not specified) were documented
in their study. Park et al\textsuperscript{11} reported 2/60 (3.3\%)
patients who underwent LAAC with the LAmbre device and suffered from PT
at days 8 and 33 after the procedure. Pericardiocentesis was required
for these two patients. A recent study with a small sample
size\textsuperscript{13} showed that 5 (29.4\%) delayed PE events
occurred in 17 patients who underwent LAAC with the LAmbre device during
3 months of follow-up. Data from LAAC with the LAmbre device are
relatively inadequate and the safety of combining LAAC with the LAmbre
device and catheter ablation is unknown. In the present study, five of
six patients with delayed PE/PT required intervention in those with the
combined procedure. Only one PE event occurred among patients with
non-PAF who underwent isolated LAAC.

The umbrella of the LAmbre device has double hooks (eight small distal
hooks engaging into the LAA wall and eight U-shaped large hooks trapping
in LAA trabeculations) with the purpose of decreasing the risk of device
embolization. However, these eight U-shaped large hooks are bare and
slender. A narrow space with widespread trabeculations in the LAA
frequently interferes with opening of the umbrella. A stronger
mechanical force against the LAA wall might develop when any of these
hooks are not fully opened. Therefore, full opening of the umbrella is
important and is considered as one of the COST criteria (including
umbrella deployed beyond the Circumflex artery; umbrella fully Open;
peri-device with optimal Sealing (leakage \selectlanguage{english}[?]3 mm) for release of the
LAmbre device; and device stability confirmed by the Tug test) for
release of the LAmbre device. The modified implantation method in which
the umbrella is initially deployed half open outside of the LAA and
complete deployment into the landing zone facilitates full opening of
the umbrella. In our study, all of the patients with delayed PE/PT
showed incomplete opening of the umbrella in fluoroscopic imaging in the
CM group. Additionally, incomplete opening of the umbrella was
significantly associated with occurrence of delayed PE/PT events as
shown in the univariate model and multivariate Cox regression analysis.
The nadir of the U-shaped hooks at the same level as the radio-opaque
marker connecting the umbrella and the cover as shown in fluoroscopic
imaging is an important sign of full opening of the umbrella. However,
this is still insufficient to guarantee an appropriate mechanical force
from the double hooks against the LAA wall because full opening of the
umbrella was found in another two patients with delayed PT in the MM
group. One of these patients required surgical management because a
small branch of the left circumflex artery was likely injured by the
small hooks. This case was considered as an exception. In patients with
the combined procedure, contractile function of the LAA was gradually
restored when sinus rhythm was maintained after the procedure. We
speculate that relative movement between the bare large hooks and the
LAA wall causing friction during sinus rhythm was the leading cause of
perforation. Therefore, we strongly recommend using this MM for patients
with the combined procedure or isolated LAAC in those with PAF.
Performance of routine echocardiographic follow-up in this patient
population may be necessary. The manufacturer of the LAmbre device might
manage with the eight U-shaped big hooks in the next-generation product
design.

\textbf{Limitations}

The retrospective, nonrandomized, single-centre design of our study has
some limitations. Because the CM group comprised the initial patients
who underwent LAAC, there might have been a learning curve, which would
be in favour of the MM group. However, PT events occurred in the
110\textsuperscript{th} and 174\textsuperscript{th} patients in the MM
group. This finding suggests there was no significant correlation
between the incidence of PE/PT and the learning curve. Additionally, the
limited number of events limited the power for our ability to detect a
significant association, as shown by the wide confidence intervals.

\textbf{Conclusions}

The conventional implantation method for the LAmbre device might be
associated with a high incidence of delayed PE/PT in patients with the
combined procedure. The MM with the intention of reducing tension from
the umbrella toward the LAA wall significantly improves the rate of full
opening of the umbrella, avoids extensive recapture of the device, and
reduces the incidence of delayed PE/PT events.

\textbf{Acknowledgements}

We thank Ellen Knapp, PhD, from Liwen Bianji, Edanz Group China
(www.liwenbianji.cn/ac), for editing the English text of a draft of this
manuscript.

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19. Wolfrum M, Attinger-Toller A, Shakir S, et al. Percutaneous left
atrial appendage occlusion: Effect of device positioning on
outcome.\emph{Catheter Cardiovasc Interv.} 2016;88(4):656-664.

Figure legends

Figure 1 Structural characteristics of the LAmbre device and umbrella
with or without full opening in fluoroscopic imaging. A) Structural
characteristics of the LAmbre device. B) The nadir of U-shaped hooks of
the device at the same level as a radio-opaque marker connecting the
umbrella and cover is a sign of full opening of the umbrella. C) The
nadir of U-shaped hooks of the device at a different level to that of a
radio-opaque marker is a sign of an umbrella without full opening.

Figure 2 Step by step illustration of implantation of the LAmbre device
in the MM group.

A) The distal umbrella was initially half deployed outside of the LAA
(defined as when a radio-opaque marker of the LAmbre device was located
between two distal marker bands at the end of the delivery sheath and it
was closer to the proximal marker band). B) Then it was gently
``en-bloc'' advanced into the proximal part of the LAA. C) Complete
deployment of the umbrella to the landing zone was subsequently achieved
by pushing out the device from the delivery sheath. D) The sheath was
withdrawn to expose the proximal cover.

Figure 3 Different opening status of the umbrella after release in
patients with delayed PE/PT. Opening status of the umbrella after
release in patients with delayed PE/PT in the CM group, including the
9\textsuperscript{th} patient (A), the 31\textsuperscript{st} patient
(B), the 42\textsuperscript{nd} patient (C), the
52\textsuperscript{nd}patient (D), and the 59\textsuperscript{th}
patient (E). Opening status of the umbrella after release in patients
with delayed PT in the MM group, including the 110\textsuperscript{th}
patient (F) and the 174\textsuperscript{th} patient (G).

Figure 4 Residual flow at first TEE follow-up A) in total; B) in
isolated LAAC; and C) in the combined procedure.\selectlanguage{english}
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