Introduction
Antithrombotic drugs, which are classified as either anticoagulants or antiplatelets,
are widely prescribed for patients with a range of cardiovascular and thromboembolic
conditions. These drugs increase bleeding risk during therapeutic endoscopic procedures
[1]
[2]
[3], and risk of thromboembolic events increases when they are discontinued [4]. There are very few reports on the association between antithrombotic agents and
endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) procedures. One prospective
controlled study comparing EUS-FNA and/or Trucut biopsy (TCB) in patients taking acetylsalicylic
acid (ASA),non-steroidal anti-inflammatory drugs (NSAIDs) and low-molecular-weight
heparin (LMWH) found that risk of bleeding in patients on antithrombotics was 33.3 %,
compared to 3.7 % in a control group [5]. A recent retrospective study from Japan included 746 patients, of whom 130 were
receiving antithrombotic therapy (ASA or cilostazol), and recorded only 1 case of
bleeding in the antithrombotic group [6].
In addition to risk of bleeding during EUS-FNA in patients taking antithrombotic drugs,
discontinuation of these agents before or during procedures is significantly associated
with an increase in thromboembolic events, such as stroke or pulmonary embolism. A
recent retrospective study of 2,197 cases of ischemic stroke identified from hospital
discharge records found that stroke ocurred in 114 patients (5.2 %) who had stopped
taking warfarin or antiplatelet agents in the previous 60 days [7].
Several guidelines for antithrombotic management in endoscopy have been proposed,
including guidelines from the British Society of Gastroenterology, the American Society
of Gastrointestinal Endoscopy, the European Society of Gastrointestinal Endoscopy
[8]
[9]
[10] and the Japan Gastroenterological Endoscopy Society (JGES) [11]. All guidelines have classified EUS-FNA as a high-risk procedure and peri-procedural
management is based on antithrombotic groups and patient risk. The most recent Japanese
guidelines (JGES) came after a consensus meeting in June 2011 where evidence-based
guidelines on management of antithrombotic therapy in endoscopy incorporate use of
oral antiplatelets and direct oral anticoagulant drugs (DOACs). These guidelines were
published in Gastroenterological Endoscopy (Japanese) in 2012 and in Digestive Endoscopy in 2014 [12]. The guidelines classified patients as high and low bleeding risk after endoscopic
procedures and investigated the factors associated with thromboembolism associated
with withdrawal of antithrombotic therapy. However, since then, very few studies have
been conducted. One retrospective study examined risk factors for early and delayed
postoperative bleeding after endoscopic submucosal dissection (ESD) of gastric neoplasms.
In patients who continued using low-dose aspirin, the bleeding risk of 9.5 % [13] was comparable to other patients.
Our study sought to evaluate the outcome of EUS-FNA, especially bleeding and thromboembolic
events, in patients receiving antithrombotic therapy, following revision of the 2011
JGES guidelines. We aimed to investigate how the relative risks of bleeding and ischemia
can be balanced after discontinuation of antithrombotic drugs.
Patients and methods
Patients
The records of 1,244 patients who were scheduled to undergo FNA between March 2013
and March 2017 at Aichi Cancer Center Hospital were reviewed and data from 908 patients
who met the inclusion criteria were analyzed. Data were collected from a computerized
database of all patients who registered and had provided written informed consent
for EUS-FNA. EUS-FNA procedures were performed by gastroenterologists or under the
supervision of a senior gastroenterologist who had been performing EUS procedures
for more than 10 years. A total of 114 patients had been taking antithrombotic drugs,
such as ASA, clopidogrel, cilostazol, dipyridamole, ticlopidine, warfarin, another
antiplatelet agent, or DOACs, for more than 1 month ([Fig. 1]). We excluded patients who had undergone an invasive high-risk endoscopic procedure
in the month prior to EUS-FNA (endoscopic retrograde cholangiopancreatography, EUS-guided
drainage, endobronchial ultrasound endoscopy, endoscopic submucosal dissection, endoscopic
mucosal resection, EUS-guided cystic analysis, etc.), because adverse events (AEs)
usually occur within this period [14]. We also excluded patients at high risk of bleeding due to bleeding disorders such
as aplastic anemia, idiopathic thrombocytopenia, thrombocytopenia, and hemophilia,
as well as those with coagulopathy or platelet dysfunction from end-stage renal disease
requiring dialysis, and those with decompensated cirrhosis.
Fig. 1 Flow diagram of patients who underwent endoscopic ultrasound-guided fine needle aspiration
and received antithrombotic therapy. ERCP, endoscopic retrograde cholangiopancreatography;
EBUS, endobronchial ultrasound bronchoscopy; EUS-guided, endoscopic ultrasound-guided;
ESD, endoscopic submucosal dissection; EMR, endoscopic mucosal resection; ASA, acetylsalicylic
acid; DOACs, direct oral anticoagulants
1 Other antiplatelets (10 ASA + thienopyridines, 10 prostaglandin, 7 ASA with thienopyridines + eicosapentane,
6 eicosapentane, 3 ASA or thienopyridines + prostaglandin, 2 cilostazol, 2 saprogrelate),
Before any decisions were made on administration of antithrombotic drugs, cases were
discussed with the primary physician before the procedure and the coagulogram (international
normalized ratio [INR] ≥ 1.5) and platelet number (> 80,000/mL) were normalized. All
patients on antithrombotic drugs were managed according to the JGES guidelines depending
on the type of drug and thromboembolic risks [11]
[12]. EUS-FNA was considered to be a high-risk procedure. Patients in the antithrombotic
group were further classified into three subgroups: 1) continuous treatment group
with patients receiving monotherapy of ASA/cilostazol and in whom non-aspirin non-thienopyridines
antiplatelets were discontinued the day of the procedure; 2) a discontinuous treatment
group, which included some patients on warfarin or DOACs who were at high risk of
bleeding but low risk of thromboembolism plus the thienopyridines group (e. g. clopidogrel
was discontinued 5 – 7 days before the procedure and ASA/cilostazol was continued
or patients switched to ASA if monotherapy); and 3) a heparin replacement group in
which warfarin was suspended and replaced with unfractionated intravenous or subcutaneous
heparin 3 to 5 days before endoscopy and then heparin suspended at least 3 to 6 hours
before endoscopy. Patients in this group who were taking warfarin or DOAC were considered
at high risk of thromboembolism. DOACs should be suspended 24 to 48 hours before the
procedure, and heparin replacement introduced 12 hours later. After temporary withdrawal
of antithrombotics, the same regimen was reestablished as soon as hemostasis was confirmed.
Generally, administration of aspirin, non aspirin antiplatelets, warfarin and heparin
should be resumed after the procedure, with warfarin or DOAC resumed when oral intake
which re-established.
The study was approved by the institutional review board of Aichi Cancer Center Hospital
(approval no. 2016-1-363).
Methods
EUS-FNA was performed with the patient in the left lateral position under conscious
sedation using intravenous midazolam (5 mg) and pethidine (25 – 100 mg). An Aloka
Prosound Alpha 10 or EU-ME2 compact ultrasound processor was used with a GF-UCT 240
or GF-UCT 260 linear array echoendoscope, (Olympus Medical Systems Corp., Tokyo, Japan).
A 19-G, 20-G, 22-G, or 25-G needle was used to perform EUS-FNA after target lesion
confirmation. During and after FNA, color Doppler imaging was performed to rule out
intervening blood vessels and signs of bleeding (new hypoechoic or hyperechoic areas)
[15]. Intraluminal bleeding was defined as blood loss from the puncture site. Negative
pressure was used with or without a 20-mL syringe in cases with an increased bleeding
risk, such as hypervascular tumors. Patient characteristics recorded included the
maximal diameter of lesions, site of lesions, route of puncture, needle size, the
number of FNA passes, underlying diseases, age, sex, lab chemistry, indication for
antithrombotic drugs, other predictive risk factors for bleeding, and length of hospital
stay. After the procedure patients’ clinical events (especially hematemesis, melena,
and thromboembolic events), vital signs, lab chemistry hemoglobin, ultrasound, computed
tomography imaging (or other imaging) were recorded within 2 to 4 weeks.
We focused on outcomes in terms of bleeding and thromboembolic events, especially
stroke and pulmonary emboli. Bleeding events and severity grading were defined according
to the definitions of the American Society for Gastrointestinal Endoscopy [14]. Significant bleeding events were defined as follows: > 2 g/dL drop in hemoglobin
level compared with baseline and/or a history of melena, hematemesis, hematochezia
with no other cause of upper gastrointestinal bleeding, or evidence of intra-abdominal
bleeding on imaging (ultrasonographic imaging reveal new hyper or hypo-echoic lesions
or bleeding evidence from computed tomography (CT) imaging. In addition, severe bleeding
was defined as cases where a transfusion and/or hemostasis by endoscopic procedure,
radiological intervention, or surgery was required. Bleeding events relating to the
procedure (classified as intraoperative bleeding) were defined as events occurring
during the procedure and up to 1 hour after the procedure. Postoperative bleeding
was defined as bleeding detected within 14 days post-procedure and delayed bleeding
after 14 days [14]. Adverse events (AEs) were graded as follow: Grade 1 mild (needs medication); Grade
2 moderate (needs ventilation, intervention, or surgery and prolonged hospital stay
of 4 – 10 days); Grade 3, severe (prolonged hospital stay of > 10 days, intensive
care unit stay of > 1 day, needs surgery, or causes disability); and Grade 4 fatal
[14].
Statistical analysis
Categorical variables were analyzed using Fisher’s exact test or the Chi-square Χ2 test. The independent sample t-test was used to compare continuous variables. Odds ratios (ORs) and 95 % confidence
intervals (95 % CI) were calculated to evaluate predictors of complications. Two-tailed
P values less than 0.05 were considered statistically significant. All calculations
were performed using SPSS version 20 (IBM Corporation, Armonk, New York, United States).
Results
Of the 908 patients undergoing EUS-FNA, 114 (12.6 %) were receiving antithrombotic
therapy while 794 (84.6 %) were not, and management of antithrombotic agents during
the EUS procedure is shown in [Fig. 1]. Baseline demographic data are shown in [Table 1]. Median age of patients in the antithrombotic group was 72 years (range, 64 – 80
years) and most were male (76 males, 38 females). The non-antithrombotic group had
a mean age of 63 years (range, 52 – 74 years) with 439 males and 355 females.
Table 1
Baseline characteristics of patients.
|
Patients data
|
ATD group (n = 114)
Mean ± SD
|
Non ATD group (n = 794)
Mean ± SD
|
P value[2]
|
|
Age
|
72 (64 – 80)
|
63 (52 – 74)
|
< 0.001[1]
|
|
Male/Female
|
76/38
|
439/355
|
0.022[1]
|
|
BMI (kg/m2)
|
21.62 ± 2.84
|
21.82 ± 3.48
|
0.557
|
|
Underlying disease[1]
|
|
|
< 0.001[1]
|
|
DM
|
38
|
347
|
|
|
HT
|
8
|
81
|
|
|
DM, HT
|
28
|
98
|
|
|
ESRD without hemodialysis
|
4
|
8
|
|
|
Decompensated Cirrhosis
|
1
|
9
|
|
|
CAD
|
21
|
1
|
|
|
CVA
|
4
|
–
|
|
|
AF
|
4
|
–
|
|
|
DVT
|
3
|
–
|
|
|
PVD
|
2
|
–
|
|
|
PE
|
1
|
–
|
|
|
Platelet count (× 104/ul)
|
21.87 ± 7.05
|
23.79 ± 12.34
|
0.105
|
|
INR
|
1.15 ± 0.15
|
1.05 ± 0.09
|
0.007[1]
|
|
Hemoglobin before FNA (g/dl)
|
12.53 ± 1.79
|
13.14 ± 1.72
|
0.001[1]
|
|
Hemoglobin after FNA (g/dl)
|
11.90 ± 1.66
|
12.47 ± 1.68
|
0.001[1]
|
|
Length of hospital stay
|
5.52 ± 7.76
|
4.30 ± 6.98
|
0.088
|
DM, diabetes mellitus; HT, hypertension; CAD, coronary arterial disease; ESRD, End-stage
renal disease; CVA, cerebrovascular disease; PE, pulmonary embolism; PVD, peripheral
vascular disease; DVT, deep vein thrombosis; Hb, hemoglobin; ATD, antithrombotic drugs;
SD, standard deviation; FNA, fine needle aspiration
1 Important underlying disease-related antithrombotic treatment. Some patients had
multiple underlying diseases
2 Statistically significant (P < 0.05)
Of the 114 patients taking antithrombotics, 42 were on ASA, 10 on clopidogrel, 2 on
ticlopidine, 10 on warfarin, 40 on other antiplatelets (10 ASA + thienopyridines,
10 prostaglandin, 7 ASA with thienopyridines + eicosapentane, 6 eicosapentane, 3 ASA
or thienopyridines + prostaglandin, 2 cilostazol, 2 saprogrelate), 8 on DOACs, and
2 on both antiplatelets and anticoagulants. Patients were divided into 3 groups based
on pharmaceutical management: 1) continuation (n = 63); 2) discontinuation (n = 41);
3) heparin replacement (n = 10) ( [Fig. 1]). Age, male sex, comorbidity, hemoglobin before and after the procedure, and INR
were significantly different in the two groups (P < 0.05); however, body mass index, platelet count, and length of hospital stay were
not ([Table 1]).
Lesion and procedure characteristics were not significantly different in the two groups.
The most common lesion puncture site was the pancreas (n = 513,56.5 %), which included
381 pancreatic cancers (42 %). The other 132 pancreatic lesions (14.5 %) comprised
53 pancreatic neuroendocrine tumors (PNETs), 30 cases of chronic pancreatitis and
benign masses, 18 of autoimmune pancreatitis, 21 macrocystis lesions (intraductal
papillary mucinous neoplasms, and solid pseudopapillary tumors), and 10 microcystic
lesions (PNETs, serous cystic neoplasms). Non-pancreatic lesions included 164 lymph
node lesions, 88 hepatobiliary tract lesions, and 143 lesions of the non-gastrointestinal
tract. Maximal diameter, puncture route, number of EUS passes, suction technique,
cystic nature, presence of ascites, and lesion vascularity were not statistically
significant between the two groups ([Table 2]).
Table 2
Baseline characteristic of procedure and final diagnosis.
|
ATD group
n = 114 (%)
|
Non ATD group
n = 794 (%)
|
Total
n = 908
|
P value
|
|
Diagnosis
|
114
|
794
|
908
|
0.280
|
|
Pancreatic lesions
|
73 (64.0)
|
440 (55.4)
|
513 (56.5)
|
|
|
Pancreatic CA
|
57 (50)
|
324 (40.8)
|
381 (42)
|
|
|
Other pancreatic disease
|
16 (14.0)
|
116 (14.6)
|
132 (14.5)
|
|
|
|
5
|
13
|
18
|
|
|
|
3
|
27
|
30
|
|
|
|
3
|
50
|
53
|
|
|
|
5
|
16
|
21
|
|
|
|
–
|
10
|
10
|
|
|
Hepatobiliary tract disease
|
11 (9.6)
|
77 (9.7)
|
88 (9.7)
|
|
|
Liver metastasis
|
4
|
25
|
29
|
|
|
CCC
|
2
|
27
|
29
|
|
|
HCC
|
1
|
3
|
4
|
|
|
GB mass/cancer
|
2
|
6
|
7
|
|
|
Other benign liver mass/cystic lesion
|
2
|
16
|
19
|
|
|
Gastroinestinal/Non-gastroinestinal mass or cancer
|
10 (8.8)
|
133 (16.8)
|
143 (15.7)
|
|
|
Gastrointestinal SMT/GIST
|
2
|
54
|
56
|
|
|
Gastroinestinal mass/cancer
|
1
|
11
|
12
|
|
|
Intra-abdominal mass/cancer
|
5
|
40
|
45
|
|
|
Intra-abdominal GIST/NET
|
2
|
11
|
13
|
|
|
Spleen/adrenal gland/lung mass
|
–
|
17
|
17
|
|
|
LN
|
20 (17.5)
|
144 (18.5)
|
164 (18.1)
|
|
|
LN metastasis
|
10
|
74
|
84
|
|
|
Other LN disease
|
7
|
47
|
54
|
|
|
Lymphoma
|
3
|
23
|
26
|
|
|
Pancreas site
|
72 (63.2)
|
444 (55.9)
|
516 (56.8)
|
0.145
|
|
Head and neck
|
26
|
167
|
193
|
|
|
Body
|
33
|
168
|
201
|
|
|
Tail
|
10
|
86
|
96
|
|
|
Multiple sites
|
3
|
23
|
26
|
|
|
Non pancreas site
|
42 (36.8)
|
350 (44.1)
|
392 (43.1)
|
|
|
Maximal diameter (Mean ± SD) (mm)
|
28.52 ± 17.43
|
28.12 ± 22.92
|
|
0.860
|
|
≤ 20 mm
|
45 (39.5)
|
316 (39.8)
|
361
|
|
|
> 20 mm
|
69 (60.5)
|
478 (60.2)
|
547
|
|
|
Puncture route
|
|
|
|
0.147
|
|
Stomach
|
64 (7)
|
504 (55.5)
|
568 (62.6)
|
|
|
Duodenum
|
36 (4)
|
185 (20.4)
|
221 (24.3)
|
|
|
Esophagus
|
7 (0.8)
|
64 (7.0)
|
71 (7.8)
|
|
|
Other
|
7 (0.8)
|
41 (4.5)
|
48 (5.3)
|
|
|
Cystic lesion
|
15 (13.2)
|
81 (10.2)
|
96 (10.5)
|
0.337
|
|
Micro-cyst
|
0
|
11
|
11
|
|
|
Macro-cyst
|
10
|
54
|
64
|
|
|
Cystic- necrosis/degeneration/retention
|
5
|
16
|
21
|
|
|
No cystic lesion
|
99 (86.8)
|
713 (89.8)
|
812 (89.4)
|
|
|
Ascites
|
|
|
|
|
|
No
|
106 (11.7)
|
770 (84.8)
|
876
|
0.082
|
|
Small
|
6 (5.3)
|
16 (2)
|
22
|
|
|
Moderate
|
2 (1)
|
8 (1)
|
10
|
|
|
Needle size
|
|
|
|
|
|
19G
|
8
|
58
|
66 (7.2)
|
0.554
|
|
20G
|
2
|
19
|
21 (2.4)
|
|
|
22G
|
93
|
668
|
761 (83.8)
|
|
|
25G
|
11
|
49
|
60 (6.6)
|
|
|
Number of needle passes (Mean ± SD)
|
2.90 ± 1.30
|
2.77 ± 1.24
|
|
0.453
|
|
≤ 2
|
51 (44.7)
|
385 (48.5)
|
436
|
|
|
> 2
|
63 (55.3)
|
409 (51.5)
|
472
|
|
|
Suction
Yes
|
107 (11.8)
|
712 (78.4)
|
819
|
0.180
|
|
No
|
7 (0.8)
|
82 (9.0)
|
89
|
|
|
Hypervascular lesion
|
|
|
|
|
|
Yes
|
6 (0.7)
|
83 (11.9)
|
89
|
0.092
|
|
No
|
108 (9.1)
|
711 (78.3)
|
819
|
|
ATD, antithrombotic drug; AIP, autoimmune pancreatitis; PNETs, pancreatic neuroendocrine
tumors; IPMC, Intraductal papillary mucinous carcinoma; SPN, solid pseudopapillary
neoplasm; SCA, serous cystadenoma; CCC, cholangiocarcinoma; HCC, hepatocellular carcinoma;
GB, gallbladder; GI, gastrointestinal ; GIST, gastrointestinal stromal tumor; NET,
neuroendocrine tumor; LN, lymph node
Significant bleeding occurred in six patients (0.7 %); four in the antithrombotic
group (0.4 %) and two in the non-antithrombotic group (0.2 %) (univariate OR, 9.59;
95 % CI, 2.12 – 43.1; P = 0.006; multivariate OR, 14.4; 95 % CI, 2.6 – 79.54; P = 0.002) ([Table 4]). All cases of bleeding cases occurred postoperation and all were confirmed by hemoglobin
drops and ultrasound or CT. None of these patients required blood transfusion and
were treated conservatively until clinical improvement and bleeding stoppage. The
four cases of bleeding (3.4 %,4/114) in the antithrombotic group (1 on ASA, 1 on ASA/clopidogrel,
1 on another oral antiplatelet, and 1 on warfarin) occurred in the continuation (3.2 %,2/63),
discontinuation(2.4 %,1/41) and heparin subgroups (10 %, 1/10)([Table 3]).
Table 3
Significant bleeding events according to antithrombotic management.
|
ATD management
|
Bleeding case
|
Total
|
% Bleed/group
|
P value
|
|
Yes
|
No
|
|
Antithrombotic group
|
4
|
110
|
114
|
(3.4 %,4/114)
|
0.601
|
|
1. Continue
|
2
|
61
|
63
|
(3.2 %,2/63)
|
|
|
|
2
|
61
|
63
|
|
|
|
2. Discontinue
|
1
|
40
|
41
|
(2.43 %,1/41)
|
|
|
|
0
|
14
|
14
|
|
|
|
|
1
|
10
|
11
|
|
|
|
|
0
|
16
|
16
|
|
|
|
3. Heparin replacement
|
1
|
9
|
10
|
(10 %,1/10)
|
|
|
Non-Antithrombotic group
|
2
|
792
|
794
|
(0.2 %,2/794)
|
|
|
Total
|
6
|
902
|
908
|
(0.7 %,6/908)
|
|
ASA, aspirin;
1 withdrew thienopyridine
Table 4
Bleeding events and other adverse events.
|
Complication of EUS-FNA
|
ATD
n = 114 (%)
|
Non-ATD
n = 794 (%)
|
Total
n = 908
|
Severity
(ASGE)
|
Univariate analysis
|
Multivariate analysis
|
|
OR(95 %CI)
|
P value[2]
|
OR(95 %CI)
|
P value[2]
|
|
Significant bleeding
(Hb drop > 2 g/dL)
|
4 (0.4)
|
2 (0.2)
|
6 (0.7)
|
Mild = 5
Mod = 1
|
9.59
(2.12 – 43.1)
|
0.006[1]
|
14.4
(2.6 – 79.54)
|
0.002[1]
|
|
Non-significant bleeding
(Hb drop ≤ 2 g/dL)
|
–
|
5 (0.6)
|
5 (0.6)
|
Mild = 5
|
1.14
(1.11 – 1.17)
|
1.000
|
–
|
0.997
|
|
Total bleeding
|
4 (0.4)
|
7 (0.8)
|
11 (1.2)
|
Mild = 10
Mod = 2
|
4.08
(1.17 – 14.19)
|
0.039[1]
|
0.24
(0.07 – 0.85)
|
0.027[1]
|
|
Cerebral infarction
|
1 (0.9)
|
–
|
1 (0.1)
|
Severe[1]
|
–
|
0.126
|
–
|
–
|
|
Hypotension
|
1 (0.9)
|
–
|
1 (0.1)
|
Mild
|
–
|
0.126
|
–
|
–
|
|
Fever
|
2 (0.2)
|
9 (1)
|
11 (1.2)
|
Mild
|
1.56
(0.33 – 7.30)
|
0.638
|
–
|
0.571
|
|
Acute pancreatitis
|
–
|
1 (0.1)
|
1 (0.1)
|
Mod
|
–
|
0.100
|
–
|
–
|
ATD, antithrombotic drugs; EUS-FNA endoscopic-guided fine-needle aspiration; Hb, hemoglobin;
ASGE, American Society of Gastrointestinal Endoscopy; OR, odds ratio; CI, confidence
interval; Mod, moderate
1 Severe (disability and prolonged)
2 Statistically significant (P < 0.05)
There were five cases of non-significant bleeding (Hb drop ≤ 2 g/dL) in the non-antithrombotic
group. Most were intraoperative bleeds confirmed by Doppler ultrasound, Three cases
had enhanced echogenicity of the peritumoral lesions, one had a submucosal hematoma,
elevated gastric mucosa at the puncture site, and a hypoechoic lesion in the gastric
mucosal layer, and one was bleeding from the puncture site accompanied by a spontaneous
self-limiting bleed. There was no need for endoscopic or surgical intervention. The
total number of bleeding events was 11, four in the antithrombotic group, and seven
in the non-antithrombotic group. The difference in bleeding rates between the antithrombotic
and non-antithrombotic groups was significantly different on univariate (P = 0.039) and multivariate analysis (P = 0.027) ([Table 4]).
Other adverse events recorded included one cerebral infarction, one case of acute
pancreatitis, 11 postoperative fever (infection unknown source), and one case of hypotension.
The patient who developed the acute cerebral infarction in the antithrombotic group
(0.9 %) was on thienopyridine due to concurrent diabetes mellitus, hypertension, and
cerebral vascular disease and switched to ASA before EUS-FNA for pancreatic cancer.
This patients restarted thienopyridine 1 day after the procedure. Four days after
the procedure, the patient developed left hemiparesis and brain magnetic resonance
imaging showed acute right middle cerebral infarction. The patient received palliative
care for 2 weeks before returning to their original hospital. The patient with hypotension
was in the anticoagulant group and was normotensive during the procedure. However,
within 24 hours, the blood pressure had dropped to 80/50 mm Hg and pulse rate to 70
to 88/min without an apparent cardiac cause or blood loss. The patient’s symptoms
resolved after appropriate hydration. The patient with acute pancreatitis developed
typical abdominal pain with an amylase level three times the upper normal limit and
CT showed diffuse pancreatic swelling, leading to a prolonged hospital stay of 4 to
10 days.
In addition, postoperative fever developed in 11 patients, two in the antithrombotic
and nine in the non-antithrombotic group (P = 0.571). The patients with significant bleeding had diagnoses of pancreatic duct
carcinoma (3 cases), PNET (2 cases), and lymphoma (1 case).
Factors associated with bleeding were analyzed ([Table 5]). Only antithrombotic use (P = 0.003) and INR (P = 0.007) were significantly higher in patients who experienced bleeding. No bleeding
events occurred in patients who were punctured with 20G and 25G needles. Length of
hospital stays was significantly longer in the significant bleeding group (13.1 days)
than the non-bleeding group (4.4 days; P = 0.003). Subgroup analysis of all bleeding cases is shown in [Table 6].
Table 5
Analysis of factors associated with bleeding.
|
Factors
|
Bleed (%)
n = 6
|
No bleed (%)
n = 902
|
P value[2]
|
OR(95 %CI)
|
|
Age, mean ± SD
|
65.71 ± 7.41
|
64.63 ± 11.43
|
0.909
|
|
|
≥ 60 Y
|
6 (0.7)
|
642 (70.7)
|
0.680
|
2.42
(0.29 – 20 – 20)
|
|
< 60 Y
|
1 (0.1)
|
259 (28.5)
|
|
|
|
Sex
Male
|
2 (0.2)
|
513 (56.5)
|
0.412
|
0.38 (0.06 – 2.08)
|
|
Female
|
4 (0.4)
|
389 (42.8)
|
|
|
|
ATD group
|
4 (0.4)
|
110 (12.1)
|
0.003[1]
|
14.4
(2.60 – 79.54)
|
|
Non-ATD
|
2 (0.2)
|
792 (87.2)
|
|
|
|
Hb (g/dl)
|
13.26 ± 1.86
|
13.06 ± 1.74
|
0.779
|
|
|
WBC (/mm3)
|
7710 ± 2383
|
6873 ± 2683
|
0.446
|
|
|
Platelets (× 104/mm3)
|
23.15 ± 6.79
|
23.55 ± 11.85
|
0.934
|
|
|
INR
|
1.15 ± 0.152
|
1.05 ± 0.091
|
0.007[1]
|
|
|
Organ of puncture
|
|
|
|
|
|
Pancreas
|
5 (0.6)
|
511 (56.3)
|
0.705
|
1.90 (0.37 – 9.89)
|
|
Non pancreas
|
2 (0.2)
|
390 (43.0)
|
|
|
|
Route of puncture
|
|
|
|
|
|
Stomach
|
5 (0.6)
|
563 (62)
|
0.419
|
3.01
(0.35 – 25.87)
|
|
Other
|
1 (0.1)
|
339 (37.3)
|
|
|
|
Maximal diameter, mean ± SD (mm)
|
|
|
|
|
|
≤ 20 mm
|
2 (0.2)
|
359 (39.5)
|
1.000
|
0.75 (0.14 – 4.15)
|
|
> 20 mm
|
4 (0.4)
|
542 (59.8)
|
|
|
|
Cystic lesion
|
|
|
|
|
|
Yes
|
2 (0.2)
|
86 (9.5)
|
0.108
|
0.108
(0.03 – 1.16)
|
|
No
|
4 (0.4)
|
816 (89.9)
|
|
|
|
Ascites
|
|
|
|
|
|
No
|
6 (0.7)
|
870 (95.8)
|
1.000
|
1.02 – 1.05
|
|
Mild
|
0
|
22 (2.4)
|
|
|
|
Moderate
|
0
|
10 (1.1)
|
|
|
|
Number of passes
|
|
|
|
|
|
≤ 2
|
3 (0.3)
|
433 (47.7)
|
1.000
|
1.08
(0.217 – 3.395)
|
|
> 2
|
3 (0.3)
|
469 (51.7)
|
|
|
|
Needle size
|
|
|
|
|
|
22G
|
5 (0.6)
|
756 (83.3)
|
1.000
|
0.96 (0.11 – 8.32)
|
|
19G
|
1 (0.1)
|
65 (7.2)
|
|
|
|
20G
|
0
|
21 (2.3)
|
|
|
|
25G
|
0
|
60 (6.6)
|
|
|
|
No. lesion punctures, mean ± SD
|
1.15 ± 0.83
|
1.19 ± 0.51
|
0.956
|
|
|
< 2
|
4 (0.4)
|
769 (84.7)
|
0.220
|
0.34 (0.63 – 1.90)
|
|
≥ 2
|
2 (0.2)
|
133 (14.6)
|
|
|
|
Suction technique
|
|
|
|
|
|
Yes
|
4 (0.4)
|
827 (91.1)
|
0.085
|
0.085
(0.033 – 1.007)
|
|
No
|
2 (0.2)
|
75 (8.3)
|
|
|
|
Hyper-vascular tumor[1]
|
|
|
|
|
|
Yes
|
2 (0.2)
|
815 (89.6)
|
0.110
|
4.68
(0.85 – 25.94)
|
|
No
|
4 (0.6)
|
87 (9.6)
|
|
|
|
Length of hospital stay
|
13.17 ± 22.49
|
4.40 ± 6.88
|
0.003[1]
|
3.08 – 14.45
|
OR, odds ratio; CI, confidence interval; SD, standard deviation; ATD, antithrombotic
drug; HB, hemoglobin; WBC, white blood cells; INR, international normalized ratio
1 Hypervascular tumor included hepatocellular carcinoma, neuroendocrine tumors, gastrointestinal
stromal tumors and carcinoid tumor
2 Statistically significant (P < 0.05)
Table 6
Subgroup analysis of bleeding patients.
|
Bleeding
|
Sex
|
Age (y)
|
U/D
|
Management ATD
|
Bleeding
|
LOS (day)
|
Blood Tx
|
Severity
|
Diagnosis
|
Organ
puncture
|
Diameter (mm)
|
Cyst
|
Ascites
|
Route
|
Needle
|
No. FNA
|
No. lesion
|
Suction
|
Hypervascular tumor
|
|
Significant bleeding
|
F
|
72
|
DM
|
–
|
Post op
|
4
|
No
|
Mild
|
PDAC
|
Pancreas
|
10
|
Y
|
N
|
Stomach
|
22G
|
2
|
1
|
Y
|
N
|
|
F
|
60
|
DM,HT, DVT
|
Heparin
|
Postop
|
6
|
No
|
Moderate
|
PNETs
|
Pancreas
|
50
|
N
|
N
|
Stomach
|
19G
|
4
|
1
|
N
|
Y
|
|
F
|
56
|
DM
|
–
|
Post op
|
3
|
No
|
Mild
|
PDAC
|
Pancreas
|
19.3
|
Y
|
N
|
Duodenum
|
22G
|
1
|
1
|
Y
|
N
|
|
M
|
75
|
DM,HT
|
continue
|
Post op
|
2
|
No
|
Mild
|
Lymphoma
|
LN
|
55
|
N
|
N
|
Stomach
|
22G
|
4
|
3
|
Y
|
N
|
|
F
|
67
|
DM
|
continue
|
Post op
|
5
|
No
|
Moderate
|
PNETs
|
Pancreas
|
30
|
N
|
N
|
Stomach
|
22G
|
5
|
2
|
N
|
Y
|
|
M
|
61
|
DM,HT, CVA
|
continue
|
Post op
|
3
|
No
|
Mild
|
PDAC
|
Pancreas
|
29
|
N
|
N
|
Stomach
|
22G
|
2
|
1
|
Y
|
N
|
|
Non-significant bleeding
|
F
|
64
|
No
|
–
|
Intraop
|
3
|
No
|
Mild
|
SCN
|
Pancreas
|
30
|
Y
|
N
|
Stomach
|
22G
|
3
|
1
|
Y
|
Y
|
|
M
|
45
|
No
|
–
|
Intraop (Submucosal hematoma)
|
3
|
No
|
Mild
|
Other lesion (sarcoid)
|
Bile duct
|
30.4
|
N
|
N
|
Stomach
|
20G
|
3
|
1
|
Y
|
N
|
|
M
|
60
|
No
|
–
|
Post op
|
2
|
No
|
Mild
|
RCC LN metastasis
|
LN
|
13.5
|
N
|
N
|
Esophagus
|
22G
|
5
|
1
|
Y
|
N
|
|
M
|
59
|
HT
|
–
|
Intra op
|
2
|
No
|
Mild
|
Pancreatic Benign
|
Pancreas
|
13.6
|
N
|
N
|
Stomach
|
22G
|
1
|
1
|
Y
|
N
|
|
F
|
67
|
DM,HT
|
–
|
Intra op (Intraluminal bleeding)
|
11
|
No
|
Mild
|
Intra-abdominal carcinoma
|
Intra-abdominal soft tissue
|
106.5
|
N
|
Y
|
Stomach Duodenum
|
22G
|
1
|
1
|
Y
|
N
|
LOS, length of hospital stay; M, male; F, female; N, no; Y, yes; DM, Diabetes mellitus;
HT, hypertension; DVT, deep vein thrombosis; CAD, coronary arterial disease; PDAC,
pancreatic duct adenocarcinoma; PNETs, pancreatic neuroendocrine tumor; SCN, serous
cystic neoplasm; RCC, renal cell carcinoma; LN, lymph node; Post op, postoperative
bleeding; Intraop, Intraoperative bleeding; Blood Tx, blood transfusion.
Discussion
A previous large systematic review of 22 studies had suggested that risk of bleeding
associated with gastrointestinal procedures in patients receiving antiplatelet therapy
was not significantly higher than in patients with interrupted antiplatelet therapy
or in those with no bleeding at all. Only five studies showed a higher risk of bleeding
during continuous antiplatelet therapy and there was only one prospective study of
241 EUS-FNA and/or TCB procedures that found bleeding in 0/26 of the ASA/NSAIDs group,
2/6 of the LMWH group, and 7/190 in the control group with no statistically significant
difference (P = 0.023). In addition, the mean number of FNA passes, applications of suction, blood
specimens, and cellular yield were not significantly different. EUS-FNA or TCB is
safe in patients taking ASA or NSAIDs [16].
In addition, bleeding risk was found to be increased according to specific types of
antithrombotic drugs, such as warfarin and heparin. A recent meta-analysis showed
that periprocedural bridging therapy with heparin increased overall risk of major
bleeding without a significant decrease in risk of thromboembolic events [16]
[17].
A previous study from Japan on EUS-FNA for solid lesions in patients on antithrombotic
therapy found that the overall bleeding event rate was 0.9 % and that all bleeding
events were intraoperative. Subgroup analysis according to antithrombotic agent revealed
bleeding event rates of 1.0 % (6/611), 0 % (0/62), 1.6 % (1/61), and 0 % (0/8) in
non-administration, discontinuation, continuation of ASA or cilostazol, and heparin
replacement groups, respectively [6]. The antithrombotic therapy group had only one case of intraoperative bleeding in
the continuous group, and bleeding risk was not related to the type or size of the
lesion, needle size, needle pass route, the number of passes, or the type of antithrombotic
therapy.
In this study the overall significant bleeding rate was 0.7 %, 0.4 % in the antithrombotic
group and 0.2 % in the non-antithrombotic group. According to subgroup classification
using the updated JGES guidelines, significant bleeding in the antithrombotic group
occurred in two cases, one case and one case of the continuation, discontinuation,
and heparin replacement groups, respectively and two cases in the non-antithrombotic
group. All bleeding in the antithrombotic group occurred postoperatively (within 1 – 14
days).Bleeding risk from antithrombotics was significantly higher (P = 0.003). Our results differ from the outcomes of a previous study [6] in that postoperative significant bleeding occurred in four cases in the antithrombotic
group and two cases in the non-antithhrombotic group. One prospective study of EUS-FNA
or Trucut biopsy in EUS-FNA reported one case of immediate bleeding and one case of
late bleeding from six cases (33.3 %) in a heparin/LMWH group but no bleeding in continued
ASA or NSAID group [5]. Another retrospective study of endoscopic submucosal dissection reported a delayed
bleeding rate in patients taking antithrombotic drugs of 11.6 %(P = 0.013) [18]. Continuation of antithrombotics in EUS-FNA may present a risk of operative or delayed
bleeding and care should be taken after the procedure.
The non-significant bleeding rate was 0.6 % and the total bleeding event rate was
1.2 %, all of which were found in the non-antithrombotic group. There were no incidences
of severe bleeding in our study. Both significant and total bleeding events were more
common in the antithrombotic group. We found that patients in the antithrombotic group
in this study were older, more commonly male, and had higher rates of comorbidity
and lower hemoglobin levels at baseline than those in the non-antithrombotic group. In
addition, one patient who was on ASA and discontinuation of thienopyridine developed
cerebral infarction. This patient had a high thromboembolism risk and restarted thienopyridine
1 day after the procedure.
There are concerns about postprocedural follow-up and length of hospital stay in patients
who experience bleeding after medication adjustment, especially when switching from
warfarin to heparin, and the need for close observation in these cases. However, after
1 month of follow-up, we recorded no instances of late death and only one case of
major morbidity (the aforementioned cerebral infarction. Factors such as maximal diameter
of the lesion, puncture route, number of EUS passes, suction technique, cystic nature,
presence of ascites, and lesion vascularity were not associated with bleeding risk.
The major limitation of this study was the low number of patients in the antithrombotic
group, especially the anticoagulant subgroup. In the future, larger prospective studies
of patients with high-risk factors such as antithrombotic therapy, especially those
taking thienopyridines or anticoagulants and those with hypervascular masses, are
needed.
Conclusion
The bleeding risk in the antithrombotic group was higher than in the non-antithrombotic
group. However, no severe bleeding was found in patients who continued or discontinued
antithrombotic therapy and only one thromboembolic event occurred. Relative risks
of bleeding and thrombosis should be carefully assessed during the preprocedural decision-making
process.
