Keywords
Endoscopic ultrasonography - Intervention EUS - Biliary tract
Introduction
Laparoscopic cholecystectomy is the gold standard treatment for patients with acute
cholecystitis (AC) [1]. However, not all patients are candidates for surgery during hospitalization for
AC. Once the episode is resolved, the patient’s baseline situation may improve, and
cholecystectomy should be performed as a preventive measure against future biliary
events. On the other hand, some patients are at high surgical risk due to comorbidities
and high anesthetic risk, a situation which does not improve after the resolution
of cholecystitis, and they will never be surgical candidates. The recommended treatment
for patients at high surgical risk is currently percutaneous gallbladder drainage
(PT-GBD), or endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) in specialized
and experienced centers [2]
[3].
Since the advent of EUS-GBD, there has been increasing evidence that it is a feasible,
safe, and effective technique comparable to PT-GBD [4]. Recent data show that EUS-GBD results in fewer adverse events (AEs) than in patients
undergoing PT-GBD, with the same rates of technical and clinical success; however,
long-term safety data beyond 2 years are not available. Similarly, there is no evidence
about the optimal follow-up strategy for these patients to achieve the minimum AE
rate for biliary events, as well as possible long-term AEs associated with the stent.
Due to their design and ease of use, lumen apposing metal stents (LAMSs) allow EUS-GBD
to be performed quickly and efficiently. Some authors advocate removing the LAMS weeks
after EUS-GBD to avoid long-term AEs associated with LAMS [4], similar to studies using LAMS in pancreatic fluid collection. In contrast, other
authors have suggested indwelling LAMS, given the fragility of these patients [5].
The aim of our study was to evaluate the very long-term efficacy and safety of EUS-GBD
with LAMS in the treatment of high-surgical-risk patients with AC.
Patients and methods
The present study was a single-center retrospective case series evaluating the long-term
outcomes of consecutive patients who underwent EUS-GBD for AC. This study was approved
by the local institutional review board (IRB). Patients were prospectively enrolled
in a LAMS registry, which includes all LAMS deployed in our center. All patients or
their legal representatives provided written informed consent.
All consecutive patients who underwent EUS-GBD for AC between September 2016 and April
2020 were eligible to participate in this study if data for a minimum of 3 years follow-up,
or until their deaths, were available. All authors had access to the study data and
reviewed and approved the final manuscript before submission.
EUS-GBD
Procedures were performed by two expert endoscopists (BMM, JRA) in the endoscopy suite.
Patients were sedated with intravenous administration of propofol by the endoscopy
team or under general anesthesia by an anesthesiologist.
The gallbladder was imaged under EUS from the antrum or duodenal bulb using a therapeutic
echoendoscope. Doppler was used to avoiding intervening vessels. In all cases, transduodenal
drainage was attempted first. Transgastric drainage was performed only when transduodenal
access was not possible, due to the absence of visualization of the gallbladder, vascular
interposition, distance to the gallbladder, smaller target size or very unstable position
of the echoendoscope.
The 10 × 10 or 15 × 10 mm LAMS (Hot Axios, Boston Scientific) was deployed directly
using a freehand technique with pure cutting current (PureCut mode 100W, effect 2,
Olympus ESG 300). The distal flange of the stent was deployed under EUS guidance,
followed by deployment of the proximal flange intrachannel. A coaxial 7F or 10F x
3 cm double-pigtail plastic stent (Boston Scientific) was inserted to prevent potential
dislodgment or occlusion by food.
In patients with previous PT-GBD, internalization of gallbladder drainage was achieved
by artificial distension of the gallbladder with infusion of saline or contrast via
the percutaneous cholecystostomy drainage tube. If the gallbladder was contracted
or large stones occupied the space, contrast or saline was injected through a 19G
or 22G EUS needle before insertion of the LAMS.
In patients with concomitant choledocholithiasis or cholangitis, endoscopic retrograde
cholangiopancreatography was performed at the same session.
Definitions
AC was diagnosed according to the Tokyo guidelines criteria based on a combination
of clinical symptoms (fever, right upper quadrant pain, positive Murphy’s sign), laboratory
data (high serum C-reactive protein, leukocytosis), and imaging findings (US, EUS,
or computed tomography [CT]) [1]. Patients who were at very high risk for cholecystectomy and underwent EUS-GBD as
a definitive treatment were included in this study. Patients were deemed very high
risk for cholecystectomy if they satisfied at least one of the following criteria:
age > 80 years, American Society of Anesthesiologists (ASA) grade ≥ 3, age-adjusted
Charlson comorbidity index > 5, Karnofsky score < 50, and/or Rockwood score 7 to 9.
All patients were evaluated by the surgeon to confirm their high surgical risk and
exclude cholecystectomy.
AEs were defined as any procedure-related event appearing during or after the procedure.
Early AEs occurred within 7 days after the procedure, and late AEs occurred 7 days
after the procedure. They were graded for severity according to the American Society
for Gastrointestinal Endoscopy severity grading system [6].
Biliary events (BEs) were defined as the occurrence of biliary colic, cholangitis,
choledocholithiasis, or acute biliary pancreatitis during follow-up. LAMS-related
AEs (LAMS-RAEs) were defined as internal or external migration of the stent, delayed
bleeding, buried stent syndrome, gastric emptying obstruction, or stent obstruction
with recurrence of AC.
For data compilation, yearly observation of imaging test and medical history were
verified. Data regarding baseline demographics and diagnosis, endoscopic procedure,
AE, migration, stent retrieval, and mortality were retrieved from the prospective
LAMS registry. In addition, all-cause emergency room visits and hospital admissions
were retrieved from electronic medical records, as well as all notes and reports made
by physicians about outpatient visits. Reports of imaging studies and all other procedures
performed were also reviewed. All post-EUS-GBD imaging tests available for each patient
from every AE or for any other reason were reviewed to assess the presence or absence
of the stent. Discharge reports after every hospital admission were also included.
After discharge from the hospital, no revisions were scheduled unless an AE or suspected
LAMS dysfunction occurred. In this case, a gastroscopy was performed. A regular endoscope
was inserted through the LAMS into the gallbladder to check for the presence of gallstones,
food, or detritus. In case of internal migration or buried stent, the LAMS was removed
and replaced with a 7F double-pigtail plastic stent or a full covered self-expanded
metal stent.
Outcome measurements
Outcome measurements included technical success, clinical success, intraprocedural
AEs, recurrent biliary events, LAMS-RAEs, recurrent cholecystitis, reinterventions,
readmissions or any medical assistance up to 3 years after the procedure, or death.
Technical success was defined as the ability to access and drain the gallbladder by
placement of a stent. Clinical success was defined as improvement in clinical symptoms
and laboratory tests.
Statistical analysis
Statistical analyses were performed using SPSS V.29.0 statistical software (SPSS,
Chicago, Illinois, United States). Descriptive statistics are reported as frequencies
(proportions) and means (95% confidence interval [CI]) or medians (interquartile range)
as appropriate. Comparisons between patients were made by χ2 test or Fisher’s exact test for categorical data, and Mann-Whitney U test and t-test
for continuous data, where appropriate.
Dysfunction-free survival was analyzed by Kaplan–Meier statistics. Patients were
censored at dysfunction, death, and last telephone follow-up – whichever came first.
Predictors of dysfunction were analyzed through Cox proportional hazards regression
and
results expressed as hazard ratios (HRs) and 95% CIs.
Results
Between September 2016 and April 2022, 68 patients were assessed for EUS-GBD, among
whom 62 patients (91.7%) were drained successfully. Twelve patients with another indication
were excluded, and the 50 patients with gallbladder drainage using Hot Axios stent
for AC were analyzed.
The reasons for technical failure were scleroatrophic gallbladder in one case, gallbladder
perforate in two cases, colon interposition in one case, and gallbladder further than
1.5 cm from the gastrointestinal tract in two cases. Clinical success was achieved
in 49 of 50 patients (98%). No intraprocedural AEs were observed, and there was only
one early AE (< 7 days) due to gastric emptying obstruction, whereas the remaining
AEs were delayed. Patient characteristics and details of the procedure are shown in
Table 1 and Table 2, respectively.
The median follow-up for all patients was 25.0 months (IQR: 1.8–38.5; range 0–57 months).
The median follow-up of patients alive at the end of the study was 41 months (IQR:
38–44.5; range 36–50 months), whereas the follow-up of patients who died during the
study was 7.7 months (IQR: 1.1–29.2; range 0–57 months). Six patients (12%) died during
the first 30 days, 20 patients (40%) at 1 year, 25 patients (50%) at 2 years, and
35 patients (70%) at 3 years. The patient who presented with clinical failure died
4 days after the procedure due to refractory sepsis. Table 3 shows all causes of death
during the follow-up.
Adverse events
The cumulative number of patients who developed AEs in the follow-up were: two (4%)
at 30 days, nine (18%) at 1 year, 10 (20%) at 2 years and 13 (26%) at 3 years. Thirteen
patients presented with 23 AEs, only three of which were severe. Table 4 shows the
AEs and their resolution in each patient and Table 5 shows details of AEs in each
category. No association was observed between the different variables analyzed for
the occurrence of complications: cirrhosis, anticoagulation, antiplatelets, Charlson
index, ASA, severity of cholecystitis, previous cholecystitis, previous percutaneous
cholecystostomy, conversion of percutaneous cholecystostomy, type of sedation, size
of stones, size of coaxial pigtail or ERCP in same session. Biliary events (BEs) and
LAMS-related AEs (LAMS-RAEs) are summarized below.
Biliary events
We found 9 BEs in six patients (11.1%), with a median occurrence of 186 days (IQR:
96–360; range: 24–743 days): six cholangitis, one choledocholithiasis, one biliary
colic, one hepatic abscess. The severity of the BEs was mild in two patients (22.2%),
moderate in four patients (44.2%), and severe in three patients (33.3%), and resolution
was endoscopic in seven cases (78%), conservative in one case (11%), and via interventional
radiology in one case (11%) requiring drainage of liver abscesses associated with
cholangitis. Most of the BEs occurred in the first year ([Fig. 1]).
Fig. 1 Kaplan–Meier curve of biliary event-free survival following endoscopic ultrasound-gallbladder
drainage.
LAMS-RAEs
We found 14 LAMS-RAEs in 11 patients (22%), with a median occurrence of 674 days (IQR:
116–777 range: 5–1229 days): three stent occlusions with recurrence of AC, two buried
stents, two gastric outlet obstructions, and seven migrations. Treatment of these
events was endoscopic in seven cases (50%), with stent cleaning in the two cases of
stent occlusion, stent removal in the two cases of buried stents and intravesicular
migration, and stent repositioning with pigtail in the patient with two episodes of
gastric outlet obstruction. In the remaining seven cases, management was conservative
(50%). Only five LAMS-RAEs (37.5%) were symptomatic, with all migrations being asymptomatic,
as well as the two cases of buried stents. LAMS were removed in four patients due
to AEs.
Three recurrences of AC were observed in two patients (4%) due to obstruction of the
stent. In one patient, the first episode was managed endoscopically by conservative
management and cleaning the stent. In the second patient, who presented with obstruction
of the LAMS by large stones, cholecystoscopy and electrohydraulic lithotripsy were
performed.
LAMS-RAEs increased over time ([Fig. 2]), but symptomatic complications developed only in the first year, and the increase
in LAMS-RAEs after the first year occurred at the expense of exclusively asymptomatic
events.
Fig. 2 Kaplan–Meier curve of LAMS-RAE-free survival following endoscopic ultrasound-gallbladder
drainage.
Although no significant association was observed for the appearance of LAMS-RAEs related
to the location of the stent in the gastric or duodenal position (P = 0.3), we observed that symptomatic LAMS-RAEs occurred in 66.7% of patients with
gastric location of the stent compared to 12.5% of symptomatic LAMS-RAEs with a duodenal
location (P = 0.03).
Migration
Thirty-eight of the 50 patients had imaging tests during follow-up (Rx abdomen, ultrasound,
CT or gastroscopy). Twelve patients did not have any imaging test at follow-up after
LAMS deployment. In six patients, the first imaging test showed the absence of a LAMS.
In the remaining 32 patients, the presence of the LAMS was confirmed by imaging or
gastroscopy.
Twelve months after LAMS deployment, we found that 19 of 30 patients who remained
alive (63.3%) had a subsequent imaging test confirming the presence of the stent at
that time. Migration of the Axios stent was evident in seven patients (14%) after
a median of 777 days (630–1077; range: 25–1229): intravesicular in one case, expulsion
into the duodenum with extraction of the stent during ERCP in one case, and by spontaneous
expulsion of the stent and casual finding in an imaging test performed for another
reason in five cases. The follow-up after migration of the LAMS was a median 304 days
(137–488; range: 11–1722), with no subsequent recurrence of cholecystitis in any of
these patients.
Delayed bleeding, antiplatelet therapy, and anticoagulation
Eighteen patients (36%) were on anti-aggregant therapy (16 aspirin, 2 clopidogrel,
1 double anti-aggregation), and 12 patients (24%) were on anticoagulation therapy:
five acenocumarol, seven direct oral anticoagulants (DOACs). Aspirin was not discontinued
for the procedure in any case. In one case, clopidogrel was replaced by aspirin; in
the other cases, clopidogrel or double antiplatelet was not discontinued. In patients
with anticoagulant treatment, the effect of acenocumarol was reversed for the procedure
and the DOACs suspended between 24 to 72 hours according to current guideline recommendations.
No episode of early or delayed gastrointestinal bleeding was recorded during the entire
follow-up.
Discussion
Data from our cohort with 3-year follow-up show that treatment of AC with placement
of LAMS by EUS-GBD without scheduled removal thereafter is safe, with a low rate of
symptomatic AEs. Moreover, there was no significant progressive increase in the AE
rate associated with EUS-GBD. Most of the BEs occurred in the first year, whereas
LAMS-RAEs increased over time. However, the only symptomatic LAMS-RAEs occurred during
the first year, and the increase after the first year occurred at the expense of exclusively
asymptomatic events. Therefore, this finding should not motivate revision or removal
of the LAMS. These data seem relevant because, even in a fragile population with a
high life expectancy, it is not unlikely that we will find patients with follow-up
much longer than 1 year. On the other hand, most AEs are resolved by endoscopy or
conservative treatment. To date, this study has the longest reported follow-up on
EUS-GBD with LAMS in patients with AC. Previous long-term reports with 1 year follow-up
do not allow the evaluation of all concerning questions about indwelling LAMS in fragile,
but not terminal, patients.
The treatment of AC depends mainly on the severity of the cholecystitis, the patient's
general condition, and comorbidity. Laparoscopic cholecystectomy is considered the
treatment of choice. In patients in whom surgery is ruled out and who do not respond
to antibiotic treatment, PT-GBD, EUS-GBD, or endoscopic transpapillary gallbladder
drainage (ETGBD) is indicated [1]. Recently, EUS-GBD has replaced PT-GBD in the treatment of high-surgical-risk patients
with AC due to better outcomes [3]
[4]. A recent multicenter prospective randomized study comparing EUS-GBD and PT-GBD
observed a significant decrease in AEs at 1 year (25.6% vs. 77.5%, P < 0.001), lower 30-day reintervention rate (2.6% vs. 30%, P = 0.001), and recurrence of cholecystitis (2.6% vs. 20%, P = 0.029), as well as lower readmission rate, post-procedural pain, and analgesia
requirements in the EUS-GBD group [4]. Recent meta-analyses corroborate these data for EUS-GBD versus percutaneous drainage
[7]
[8]. Similarly, EUS-GBD has shown better results compared to ETGBD, with a higher technical
and clinical success rate, as well as a lower rate of AC recurrence with no differences
in AEs [9]
[10]. Our results with 91.7% technical success and 98% clinical success corroborate the
data published previously [11]
[12].
However, there is no established recommendation for subsequent management of patients
once EUS-GBD has been performed. Some authors have suggested a proactive strategy
of direct peroral cholecystoscopy and complete stone clearance, allowing removal of
the LAMS with or without double-pigtail replacement [4]
[11]. This strategy may prevent AEs associated with indwelling LAMS, such as delayed
bleeding, buried stent, ingrowth or overgrowth, migration, and other complications.
However, many patients ultimately do not undergo revision because they are fragile.
In the DRAC1 study, only 67.5% of patients underwent revision because the rest of
the patients were too fragile and rejected this option. In addition, in 88.9% of the
patients who underwent revision, spontaneous passage of lithiasis was observed without
a need for additional endoscopic measures [4]. In the study by Irani SS et al., LAMS were removed in only 63.3% of the patients,
due to fragility or comorbidity in 26.7% of the patients [12]. Furthermore, complete gallbladder cleansing can be challenging. In a study reported
by Chan et al., a mean of 1.25 sessions of cholecystoscopy were needed for a complete
stone clearance rate of 88% [13]. In this study, 56% of the patients had spontaneous stone passage on cholecystoscopy
after EUS.
For this reason, we chose a strategy of indwelling EUS-GBD and placement of a coaxial
double-pigtail stent to avoid obstruction of the stent by food or lithiasis, with
endoscopic revision only in cases with or suspected of AEs. With this strategy, we
observed a total AE rate of 18% after the first year, lower than that reported in
the DRAC1, which had a total complication rate of 25% [4]. Furthermore, the recurrence rate for cholecystitis of 4% in our series is similar
to the recurrence rates for cholecystitis observed in studies with shorter follow-up
periods, which range from 2.6% to 7% [4]
[12]
[14]
[15]. Thus, a strategy of indwelling LAMS seems comparable in the short term to a strategy
of proactive cholecystoscopy and complete stone clearance, which would obviate the
need for systematic endoscopic revision in patients at high surgical risk who undergo
EUS-GBD. Clearly, these data are superior to a conservative strategy, as shown in
a 2-year follow-up study of 197 patients with AC who did not undergo surgery but had
a 38.5% BE rate and 27% recurrence rate for cholecystitis [16].
There are few long-term data on EUS-GBD, with published follow-up periods of only
1 year [4]
[12]. The only study published to date with a follow-up of more than 1 year is the study
by Yuste et al. [5] in which 22 patients were included with a median follow-up of 24.4 months (IQR:
18.2–42.4), but patients who had not completed a follow-up of at least 12 months were
excluded, which could imply bias as the first year is the period of time when most
BEs occur in our series. Nevertheless, using a protocol similar to ours without systematic
endoscopic review, the authors concluded that indwelling LAMS is a definitive treatment
in non-surgical patients.
Although we found no significant differences between the duodenal or gastric route
in the occurrence of LAMS-RAEs, we did observe an increase in symptomatic LAMS-RAEs
associated with gastric placement of the LAMS (66.7% vs. 12.5%, P = 0.03), so this group of patients could potentially benefit from a strategy of revision,
eventual cleaning of the gallbladder, and removal or replacement of the LAMS with
a pigtail. Similarly, 46.2% of the patients who presented with AEs developed a second
episode that was symptomatic in 83.3%, so we consider that, once a patient presents
an AE, it would be advisable to perform endoscopic revision with LAMS removal to avoid
successive AEs.
One of the concerns about leaving a LAMS permanently is the possibility of delayed
bleeding, which occurs in pancreatic collections drained with LAMS when the stent
is maintained for a long time [17]. In our series, we found no cases of gastrointestinal bleeding, despite the fact
that 36% of the patients were on antiplatelet therapy and 24% of patients were receiving
anticoagulation therapy. This reflects the safety of EUS-GBD even in anticoagulated/anti-aggregation
patients and rules out the need to remove the gallbladder stent due to the risk of
bleeding associated with LAMS.
Regarding migration, we found a rate of 14% in our series, higher than in other published
series [4]
[5]. However, this is justified by most migrations occurring late in our series with
a median time to migration of 777 days. However, none of the patients had recurrence
of cholecystitis. One possible explanation is that migration occurs when the gallbladder
has been spontaneously cleared due to collapse of the gallbladder, which is why new
episodes of AC would not occur.
Our study has some limitations, such as the fact that it is a retrospective review
of a prospectively maintained database, so that events that have not motivated the
medical consultation could go unnoticed, although information about the relevant events
that would motivate the medical visit would be collected. Furthermore, it is the experience
of a single center, so the high technical success rates could be affected in centers
with less experienced endoscopists.
Conclusions
In conclusion, the current study provides definitive data that confirm that EUS-GBD
with indwelling LAMS in high-surgical-risk patients is an effective and safe technique
in the long term. Based on our results, most patients do not require endoscopic revision
and removal of the stent, and this strategy is reserved for those who present with
a first complication or in cases in which drainage is performed through the stomach.
However, comparative studies with a strategy of an indwelling stent or removal of
the LAMS would be required to confirm these findings.
