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World Journal of
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World Journal of
WJ G E Gastrointestinal
Endoscopy
Contents Monthly Volume 12 Number 6 June 16, 2020
REVIEW
172 Management of antiplatelet or anticoagulant therapy in endoscopy: A review of literature
Maida M, Sferrazza S, Maida C, Morreale GC, Vitello A, Longo G, Garofalo V, Sinagra E
CASE REPORT
193 Repeat full-thickness resection device use for recurrent duodenal adenoma: A case report
Gericke M, Mende M, Schlichting U, Niedobitek G, Faiss S
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Contents
Volume 12 Number 6 June 16, 2020
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Submit a Manuscript: https://www.f6publishing.com World J Gastrointest Endosc 2020 June 16; 12(6): 172-192
DOI: 10.4253/wjge.v12.i6.172 ISSN 1948-5190 (online)
REVIEW
Management of antiplatelet or anticoagulant therapy in endoscopy:

A review of literature
Marcello Maida, Sandro Sferrazza, Carlo Maida, Gaetano Cristian Morreale, Alessandro Vitello,
Giovanni Longo, Vincenzo Garofalo, Emanuele Sinagra
ORCID number: Marcello Maida Marcello Maida, Gaetano Cristian Morreale, Alessandro Vitello, Vincenzo Garofalo,
(0000-0002-4992-9289); Sandro Gastroenterology and Endoscopy Unit, S. Elia-Raimondi Hospital, Caltanissetta 93100, Italy
Sferrazza (0000-0002-7595-0129);
Carlo Maida (0000-0002-4868-9033); Sandro Sferrazza, Gastroenterology and Endoscopy Unit, Santa Chiara Hospital, Trento 38123,
Gaetano Cristian Morreale Italy
(0000-0001-8954-7819); Alessandro
Vitello (0000-0001-9099-9468); Carlo Maida, U.O.C di Medicina Interna con Stroke Care, Dipartimento di Promozione della
Giovanni Longo Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G.
(0000-0002-3475-5968); Vincenzo D’Alessandro”, University of Palermo, Palermo 93100, Italy
Garofalo (0000-0002-6769-4778);
Emanuele Sinagra Giovanni Longo, Cardiology Unit, S. Elia-Raimondi Hospital, Caltanissetta 93100, Italy
(0000-0002-8528-0384).
Emanuele Sinagra, Gastroenterology and Endoscopy Unit, Istituto San Raffaele Giglio, Cefalù
Author contributions: Maida M, 90015, Italy
Sferrazza S and Sinagra E are
guarantors of the integrity of the Corresponding author: Marcello Maida, MD, Doctor, Gastroenterology and Endoscopy Unit, S.
entire study and contributed to the Elia-Raimondi Hospital, Via Giacomo Cusmano 1, Caltanissetta 93100, Italy.
manuscript drafting and
[email protected]
manuscript revision for relevant
intellectual content. All authors
contributed to the manuscript
editing and had full control over
the preparation of the manuscript. Abstract
Endoscopic procedures hold a basal risk of bleeding that depends on the type of
Conflict-of-interest statement: The
procedure and patients’ comorbidities. Moreover, they are often performed in
authors have no proprietary,
financial, professional or other patients taking antiplatelet and anticoagulants agents, increasing the potential
personal interest of any nature or risk of intraprocedural and delayed bleeding. Even if the interruption of
kind in any product, service antithrombotic therapies is undoubtful effective in reducing the risk of bleeding,
and/or company that could be the thromboembolic risk that follows their suspension should not be
construed as influencing the
underestimated. Therefore, it is fundamental for each endoscopist to be aware of
position presented in, or the
review of this manuscript. the bleeding risk for every procedure, in order to measure the risk-benefit ratio
for each patient. Moreover, knowledge of the proper management of
Open-Access: This article is an antithrombotic agents before endoscopy, as well as the adequate timing for their
open-access article that was resumption is essential.
selected by an in-house editor and
fully peer-reviewed by external This review aims to analyze current evidence from literature assessing, for each
reviewers. It is distributed in
procedure, the basal risk of bleeding and the risk of bleeding in patients taking
accordance with the Creative
Commons Attribution antithrombotic therapy, as well as to review the recommendation of American
NonCommercial (CC BY-NC 4.0) society for gastrointestinal endoscopy, European society of gastrointestinal
license, which permits others to endoscopy, British society of gastroenterology, Asian pacific association of
distribute, remix, adapt, build gastroenterology and Asian pacific society for digestive endoscopy guidelines for
upon this work non-commercially, the management of antithrombotic agents in urgent and elective endoscopic
WJGE https://www.wjgnet.com 172 June 16, 2020 Volume 12 Issue 6

Maida M et al. Management of anticoagulants in endoscopy
and license their derivative works procedures.

on different terms, provided the
original work is properly cited and
the use is non-commercial. See: Key words: Antiplatelet; Anticoagulant; Endoscopy; Management; Bleeding; Risk
http://creativecommons.org/licen
ses/by-nc/4.0/ ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
Manuscript source: Invited
manuscript Core tip: Endoscopic procedures hold a basal risk of bleeding, and they are often
performed in patients taking antiplatelet and anticoagulant agents, increasing the
Received: February 27, 2020 potential risk of intraprocedural and delayed bleeding. This review aims to analyze
Peer-review started: February 27, current evidence from literature assessing, for each procedure, the basal bleeding risk
2020
and the risk of bleeding in patients taking antithrombotic therapy, as well as to review
First decision: April 22, 2020
the recommendation of international guidelines for the management of these agents in
Revised: May 9, 2020
urgent and elective endoscopic procedures.
Accepted: May 19, 2020
Article in press: May 19, 2020
Published online: June 16, 2020
Citation: Maida M, Sferrazza S, Maida C, Morreale GC, Vitello A, Longo G, Garofalo V,
P-Reviewer: Hu B, Huang LY, Sinagra E. Management of antiplatelet or anticoagulant therapy in endoscopy: A review of
Sporea I literature. World J Gastrointest Endosc 2020; 12(6): 172-192
S-Editor: Zhang H URL: https://www.wjgnet.com/1948-5190/full/v12/i6/172.htm
L-Editor: A DOI: https://dx.doi.org/10.4253/wjge.v12.i6.172
E-Editor: Liu MY
INTRODUCTION
Endoscopic procedures are commonly performed in patients taking antiplatelet and
anticoagulants agents. These antithrombotic medications reduce thromboembolic
events by inhibiting platelet aggregation and coagulation and are the most widely
prescribed agents in both primary and secondary care in many patients[1]. In addition,
a growing number of subjects have an indication for combination therapy which
increases the overall risk of bleeding, in particular, that from the gastrointestinal
tract[2].
This review aims to analyze current evidence from literature assessing, for each
procedure, the basal bleeding risk and the risk of bleeding during antithrombotic
therapy, as well as to review the recommendation of American society for
gastrointestinal endoscopy (ASGE)[3], European society of gastrointestinal endoscopy,
British society of gastroenterology (ESGE/BSG) [4] , Asian pacific association of
gastroenterology and Asian pacific society for digestive endoscopy
(APAGE/APSDE) [5] for the management of antithrombotic agents in urgent and
elective endoscopic procedures.
ANTITHROMBOTIC THERAPIES
Antithrombotic therapies may be classified in antiplatelet agents (APA) and
anticoagulants.
Antiplatelets
APA interfere in specific steps of platelets activation process and include several
agents namely aspirin [acetylsalicylic acid (ASA)], nonsteroidal anti-inflammatory
drugs (NSAIDs), P2Y12 platelet receptor blockers and other agents such as
glycoprotein IIb/IIIa antibodies and receptor antagonists and the competitive and
selective inhibitors of protease-activated receptor-1.
ASA is used to inhibit platelet aggregation by irreversibly blocking the
cyclooxygenase pathway, resulting in the suppression of prostaglandin and
thromboxane biosynthesis from arachidonic acid in platelets. After cessation of ASA,
7 to 9 d are required to fully recover the platelet function. Dipyridamole reversibly
prevents platelet activation by multiple mechanisms, including the inhibitions of
cyclic nucleotide phosphodiesterase and the blocking of the adenosine uptake.
Dipyridamole has an elimination half-life of 12 h and a duration of action of about
two days after discontinuation. Thienopyridine agents represent the most common
antiplatelet drugs used following ASA. These agents selectively inhibit adenosine
diphosphate-induced platelet aggregation, with no direct effects on the metabolism of
arachidonic acid[6]. The class of P2Y12 platelet receptor blockers is broad and include

ticlopidine, clopidogrel and the most recent third-generation thienopyridine agents

such as prasugrel and ticagrelor. Ticlopidine, clopidogrel and prasugrel are prodrugs
which achieve their antiplatelet effects through active metabolites irreversibly
inactivating the P2Y12 receptor. The hepatic metabolism of prasugrel is more rapid
(occurs in a single hepatic step) and less influenced by cytochrome P450
polymorphisms than clopidogrel[7,8]. Prasugrel and ticagrelor induce a more rapid and
pronounced inhibition of platelet aggregation compared to clopidogrel. Unlike the
other thienopyridine which requires discontinuation of at least 5 to 7 d to recover
adequate platelet function, ticagrelor induce reversible inhibition of the P2Y12
receptor which permits a shorter interval of interruption (3 to 5 d)[9]. Other antiplatelet
medications include the antagonists of the platelet glycoprotein (GP)IIb/IIIa (e.g.
abciximab, roxifiban, eptifibatide, tirofiban, orbofiban, sibrafiban) which play their
antiplatelet effects by blocking the final common pathway of platelet aggregation.
Current guidelines recommend antiplatelet agents for the secondary prevention of
cardiovascular disease[10]. Conversely, these drugs are not recommended for the
primary prevention of cardiovascular disease, even if some evidence weakly supports
the advantage of aspirin in patients with hypertension and impaired renal function or
who are at high cardiovascular risk (10-year risk > 20%)[11,12].
Anticoagulants
Anticoagulants are prescribed in several clinical setting such as the prevention of
stroke in patients with atrial fibrillation and as prophylaxis and treatment of venous
thromboembolism. These drugs prevent the clotting of blood by inhibiting one or
more steps in the coagulation cascade through several mechanisms of actions
including both direct and indirect enzymatic blocking, the antagonism of vitamin
K–dependent clotting factors and the binding to antithrombin. Available drugs
include unfractionated heparin, low molecular weight heparins, fondaparinux,
vitamin K antagonists (e.g. warfarin), direct factor Xa inhibitors (e.g. rivaroxaban,
apixaban, edoxaban) and direct thrombin inhibitors which prevent thrombin from
cleaving fibrinogen to fibrin and include both parenteral agents (bivalirudin,
argatroban and desirudin) and oral agent (dabigatran etexilate). The efficacy and the
bleeding risk related to the use of anticoagulants depends on the drug used and the
clinical setting[13].
Data from the pivotal clinical trials (RE-LY, ROCKET AF, ARISTOTLE, and
ENGAGE AF-TIMI 48) suggest that direct oral anticoagulants (DOACs) are not
inferior to warfarin for the prevention of stroke or systemic embolism in subjects with
non-valvular atrial fibrillation and that these drugs also had significant reductions in
hemorrhagic stroke and intracranial hemorrhage compared to warfarin, resulting in a
lower risk of stroke and mortality[14]. Furthermore, DOACs were associated with less
severe major bleedings than those related to warfarin. Nevertheless, the rates of
gastrointestinal (GI) bleeding are increased in non-valvular atrial fibrillation patients
treated with DOACs and in particular with dabigatran 150 mg bid, rivaroxaban, and
edoxaban, but it seems to occur the least in patients receiving apixaban compared
with vitamin K antagonists therapy[15]. In this regard, Abraham et al[16] reported that
the rates of GI bleeding were significantly increased with rivaroxaban than dabigatran
(HR 1.20: 95%CI: 1.00-1.45), whereas apixaban was associated to a lower risk of GI
bleeding than dabigatran (HR 0.39: 95%CI: 0.27-0.58; P < 0.001) or rivaroxaban (HR
0.33: 95%CI: 0.22-0.49; P < 0.001). However, despite the risk of bleeding associated
with DOACs, this risk is counterbalanced by their effectiveness in preventing the risk
of stroke that is considered by patients as a “fate worse than death"[17]. A specific
antidote is available for dabigatran (idarucizumab)[18], but not for the others DOACs.
Recently, a direct factor Xa inhibitor has shown promising results against
rivaroxaban, apixaban and edoxaban (andexanet alfa)[19].
RISK OF BLEEDING ASSOCIATED WITH ENDOSCOPIC

PROCEDURES
The risk of bleeding associated with endoscopic procedures is variable and depends
mainly on the type of procedure performed (diagnostic, low-risk or high-risk
operative), on the type of antiplatelet or anticoagulant therapy and patient’s
comorbidities. In the following paragraphs, we will review and discuss, for each
procedure, the evidence from literature assessing the risk of basal bleeding and the
risk of bleeding in patients taking antithrombotic agents.
Diagnostic endoscopy
Diagnostic procedures as esophagogastroduodenoscopy (EGD), colonoscopy or

sigmoidoscopy, including mucosal biopsy, present a low-risk of procedural bleeding,

as shown by several studies[20-21].
Similarly, the risk of bleeding during diagnostic endoscopy is not increased in
patients assuming ASA, clopidogrel or warfarin. In this regard, a prospective, single-
blind, randomized study in healthy volunteers, showed that on a sample of 405 antral
biopsies and 225 duodenal biopsies performed during 90 EGD in 45 subjects receiving
aspirin or clopidogrel, no bleeding events were noted in the clopidogrel group after
350 biopsies, while in the aspirin group, only one minor endoscopic bleeding event
was reported, in the absence of clinical events[22].
Moreover, a prospective single-arm study including 112 Japanese outpatients
receiving antithrombotic agents showed that after 101 biopsies performed during
EGD or colonoscopy, no patients complained of any bleeding symptoms in the
following 2 wk observation period. In addition, the authors didn’t find significant
differences between patients receiving single and multiple antithrombotic agents, as
well as between patients not receiving and receiving warfarin[23].
Conversely, no data is currently available on the risk of bleeding after biopsies in
patients taking DOACs.
A retrospective multicenter study of double-balloon enteroscopy complications
performed in the United States reported a risk of gastrointestinal bleeding of 0.2%
associated with the procedure[24]. Unfortunately, no studies assessing the risk of
bleeding during double-balloon enteroscopy in patients on antiaggregant or
anticoagulant therapy have been performed up to date. In the absence of data, the risk
is uncertain, and it may be assimilated to that of other endoscopic diagnostic
procedures.
Polypectomy
Polypectomy may be complicated by intraprocedural or immediate bleeding (IPB)
and by post-procedural bleeding (PPB). While IPB is often self-limited and may be
controlled during the procedure, conversely, PPB may be worrisome, since it arises
after the procedure when the patient has already been discharged.
Data from large series show a PPB ranging from 0.07% to 2.2%[25-28]. A large report
from the English National Health Service Bowel Cancer Screening Programme shows
an overall bleeding rate of 0.65%, a rate of severe bleeding requiring transfusion of
0.04%, and an increased bleeding risk attributable to polypectomy of 11.1-fold[29].
Exploring factors associated with PPG, a prospective, cross-sectional study of 5152
patients undergoing polypectomy, showed that age ≥ 65 years, cardiovascular or
chronic renal disease, anticoagulants use, polyp size > 1 cm, pedunculated polyp or
laterally spreading tumors, poor bowel preparation and use of pure cutting current
were risk factors for PPB[30]. Another case-control study confirmed that polyp size was
associated with PPG, with an increased risk of hemorrhage of 9% for every 1 mm
increase in polyp diameter (OR 1.09: 95%CI 1.0-1.2; P = 0.008)[31].
Post-polypectomy bleeding in patients on antithrombotic therapy has a different
impact. The risk in patients on ASA or NSAID is generally considered low.
One of the first studies performed in this field showed as the risk of bleeding did
not seem to be affected by NSAID use. Although the use of NSAIDs increased the
incidence of minor self-limited bleeding, an increase in the rate of major bleeding was
not observed [ 3 2 ] . Besides, a revision of a cohort of 5593 patients and 1657
polypectomies clearly showed that the use of antiplatelet agents during polypectomy
was not associated with an increase in post-polypectomy bleeding[33].
A prospective multicenter trial, including a total of 1015 polyps < 10 mm removed
by cold snare in 823 patients, 15% of them taking low dose aspirin or ticlopidine,
reported a higher PPB in patients taking APA (6.2 % vs 1.4 %; P < 0.001). Nevertheless,
all bleeding episodes were intraprocedural and successfully treated, while no delayed
PPB occurred[34].
Although low in patients receiving aspirin or NSAID, the risk of post-polypectomy
bleeding is higher in patients receiving thienopyridine or warfarin.
Despite some studies advocate a low-risk of post-polypectomy bleeding in patients
taking thienopyridine[35], a meta-analysis of 5 observational studies including 574
subjects on clopidogrel therapy and 6169 controls showed an overall higher risk of
PPB on continued clopidogrel (RR 2.54, 95%CI: 1.68-3.84, P < 0.00001), with a non-
significant risk of immediate bleeding (RR of 1.76, 95%CI: 0.90-3.46, P = 0.10) and a
significantly higher risk of delayed bleeding (RR of 4.66, 95%CI: 2.37-9.17, P <
0.00001)[36].
While patients on anticoagulation therapy may safely undergo colonoscopy,
current practice guidelines consider polypectomy a high-risk procedure for which
anticoagulation must temporarily be discontinued. Despite this, the risk estimate of
bleeding is difficult to quantify with accuracy, since it depends on many variables,
especially by the size of the polyp to be removed and International Normalized Ratio

(INR) values.
A small single-center retrospective study performed on 21 patients receiving long-
term anticoagulation with warfarin with an average INR of 2.3 and undergoing
polypectomy, reported no episodes of PPB[37].
Another retrospective study supported the safety of polypectomy of small polyps <
10 mm without interruption of anticoagulation showing that, in a sample of 225
polypectomies with subsequent prophylactic placement of hemoclips, the rate of
severe PPB requiring transfusion and of minor PPB not requiring treatment were 0.8%
and 1.6%, respectively[38].
Similarly, a Japanese prospective controlled trial of 70 patients randomized to cold
snare or traditional polypectomy of lesions up to 10 mm without interruption of
warfarin, confirmed that the incidence of PPB after cold snare resection was
acceptable reporting a lower incidence of immediate (5.7% vs 23.0%) and delayed (0%
vs 14%) bleeding compared to traditional polypectomy, even without interruption of
anticoagulant therapy[39]. Despite this, further data are needed in order to properly
assess the setting in which a polypectomy on warfarin therapy could be performed
safely.
To date, current guidelines recommend discontinuing warfarin 5 d before high-risk
endoscopic procedures in patients at low thrombotic risk and discontinuing warfarin
5 d before high-risk endoscopic procedures with low molecular weight heparin
(LMWH) bridging in patients at high thrombotic risk. In this regard, also the role of
bridging need to be better assessed, as recent data suggest that patients undergoing
bridging with LMWH are at higher risk of procedural-related bleeding compared to
patients not undergoing bridging with LMWH or continuing warfarin therapy[40,41].
On the same line, a recent study showed as patients discontinuing anticoagulant with
LMWH bridging, as suggested by guidelines, had a higher PPB rate compared to
patients continuing anticoagulants (19.6% vs 10.8%, P = 0.087)[42]. Based on these
observations, recommendation on bridging therapy should be revised, and the choice
should be individualized, taking into account the hemorrhagic and thromboembolic
risk of each patient.
With regard to DOACs, the risk of PPB is not well known. The aforementioned
study, comparing post-polypectomy complication rates in 218 patients receiving oral
anticoagulants (73 DOACs, 145 warfarin) and 218 patients not receiving anticoagulant
therapy, showed that the PPB was similar between DOACs and warfarin and higher
for both compared with controls (13.7% vs 13.7% vs 0.9%, P < 0.001)[42].
Similarly, the second mentioned analysis of 11504 comparing patients on
antithrombotic therapy (1590 DOACs, 3471 warfarin, and 6443 clopidogrel) and
599983 control undergoing colonoscopy with polypectomy or endoscopic mucosal
resection, showed that subjects undergoing DOACs did not have a statistically
significant increased risk gastrointestinal bleeding, as well as cerebrovascular accident
or myocardial infarction and hospital admissions compared with controls. On the
contrary, clopidogrel and warfarin were associated with increased odds of PPB,
cerebrovascular accident or myocardial infarction and hospital admissions compared
with controls[43].
Endoscopic mucosal resection

The overall risk of intraprocedural and delayed bleeding after endoscopic mucosal
resection (EMR) has been estimated between 3.7%-11.3 % and 0.6%-6.2 %,
respectively, and it is, therefore, higher compared with polypectomy[4].
The risk of bleeding after EMR is associated with the location and the size of the
lesion. Esophageal EMR has a greater risk of bleeding ranging from 4% to 20%[44-47].
Moreover, a retrospective study showed as esophageal EMR (OR = 2.5, 95%CI: 1.2-5, P
= 0.0009) and lesion size (OR = 1.24, 95%CI: 1.1–1.5, P = 0.003) were independently
associated with a higher risk of early bleeding in EMR, when controlled for age,
gender and NSAIDs or clopidogrel therapy[48]. Besides, duodenal EMR presents a risk
of delayed bleeding between 6.3 and 12.3[47,48]. The risk of hemorrhages seems to be
lower for EMR of lesions smaller than 1 cm[49].
A delayed bleeding prediction model (GSEED-RE2), taking into account several
variables including lesion size, proximal location, comorbidity, and antiplatelet or
anticoagulant therapy, has been recently proposed showing higher values of area
under the curve (0.69-0.73; 95%CI: 0.59-0.80) compared to previous models[50].
Prophylactic measures may help to reduce the risk of delayed bleeding after EMR,
for instance, with the placement of hemoclips. In this regard, a retrospective study of
524 lesions 2 cm or larger resected by EMR showed that the delayed bleeding rate was
1.8% in the clipped group vs 9.7% in the not clipped group and that the absence of
clipping (OR = 6.0; 95%CI: 2.0-18.5) was independently associated with delayed
hemorrhage[51]. On the other hand, the other two studies did not find any significant
difference in the rate of PPB between patients with and without prophylactic

placement of hemoclips[52,53].
Concerning the risk of bleeding associated with antiplatelet therapy, data from two
large prospective intention-to-treat studies of 302 EMR for colonic laterally spreading
tumors ≥ 20 mm performed in 288 patients, showed that the use of aspirin (OR = 6.3, P
= 0.005), was independently associated with the risk of bleeding at multivariate
analysis[54]. On the contrary, temporary discontinuation of anticoagulants seems to be
safe. A retrospective study on a cohort of 798 patients undergoing 1716 EMR, all of
them stopping antiplatelets and anticoagulants 7 d before EMR and resuming
clopidogrel 2 d after EMR, showed that the temporary cessation of clopidogrel before
EMR and its prompt resumption was not associated with an increased risk of
gastrointestinal bleeding[55]. No data is available for other anticoagulants, including
DOACs, for the risk of bleeding after EMR.
Based on these data, EMR is considered a high-risk endoscopic procedure for the
management of anticoagulant therapy.
Endoscopic submucosal dissection

Endoscopic submucosal dissection (ESD) is a more recent and more complex
technique, with growing popularity worldwide. Although a more radical resection,
the risk of IPB and of PPB seems to be higher compared to EMR. A meta-analysis of 15
non-randomized studies comparing ESD with EMR confirmed higher “en bloc”
resection rates (OR = 13.87, 95%CI: 10.12-18.99) and higher curative resection rates for
ESD compared to EMR (OR = 3.53, 95%CI: 2.57-4.84), with the disadvantage of higher
procedure-related bleeding (OR = 2.20, 95%CI: 1.58)[56].
Nevertheless, the risk is lower for esophageal and colonic ESD, and higher for
gastric ESD. A meta-analysis of 15 studies with a total of 776 ESD procedures
performed for resection of esophageal neoplasia showed a pooled estimate of PPB of
2.1% (95%CI: 1.2-3.8)[57]. Similarly, in another meta-analysis of 22 studies with a total
of 2841 colonic ESD, the pooled estimate of PPB was 2.0% (95%CI: 1.0-2.0)[58].
On the contrary, gastric ESD presents a risk of PPB ranging from 3.6% to 6.9% as
reported in 7 studies, including > 11000 procedures[59-65].
With regard to the risk of bleeding associated with antiplatelet therapy, most of the
data come from gastric setting. In patients who do not discontinue aspirin before
gastric ESD, aspirin use is independently associated with PPB (RR 4.49; 95%CI: 1.09-
18.38)[66]. The risk of bleeding in patients who discontinue aspirin before gastric ESD is
controversial. Some studies show that the risk of bleeding is increased even after its
temporary withdrawal[67,68], while other studies showed that its discontinuation is not
independently associated with delayed bleeding after the procedure[69,70]. Similarly, in
colorectal ESD, discontinuation of antiplatelet therapy is not associated with post-
procedural bleeding[71,72]. Beyond aspirin, no consistent data is available on the effect
of other agents, such as clopidogrel, ticagrelor and DOACs, on the risk of bleeding
associated with ESD.
Endoscopic dilatation
According to current literature data, no significant risk of bleeding is reported neither
in esophageal dilations[73-77] nor in those of the colon[78-84]. Besides, no study evaluated
so far the risk of bleeding due to endoscopic dilatation in patients under APA or
anticoagulant therapy.
Endoscopic stenting
The risk of bleeding after endoscopic stenting is still controversial, and it is difficult to
assess precisely, due to heterogeneity of the type of stent, the anatomical site and the
indication (benign vs malignant).
With regard to esophageal stenting, several studies report a risk of bleeding
ranging between 1% and 8%[85,86].
Besides, in the setting of gastroduodenal stenting, a systematic review of 32 case
series of stent placement in 606 patients with malignant symptomatic gastroduodenal
obstruction showed an incidence of bleeding of 0.5%[87].
Moreover, two systematic reviews assessed the incidence of bleeding in colonic
stenting. The first one, evaluating 29 case series and 598 stent placements, showed a
4.5% bleeding rate[88]. The second, including 54 non-randomized studies with the use
of stents in a total of 1198 patients, did not report any case of bleeding[89].
Also in this case, no study evaluated so far the risk of bleeding due to endoscopic
stenting in patients taking APA or anticoagulants.
Percutaneous endoscopic gastrostomy

Percutaneous endoscopic gastrostomy (PEG) is performed through the perforation of
the abdominal and the anterior stomach walls. Therefore, bleeding from some vessel
placed in the path of the puncture or, rarely, a hematoma of the wall, may occur. A

recent multicenter prospective cohort study, including 950 patients undergoing PEG
placement or replacement, showed a 1% bleeding rate[90].
In another retrospective, single-center study of 990 patients undergoing PEG
placement, the incidence of bleeding was 1.6%, and multivariate analysis
demonstrated no association between periprocedural use of aspirin (at any dose) or
clopidogrel and post-PEG bleeding[91].
Also in this setting, no data is available on the risk of bleeding after PEG placement
in patients taking prasugrel, ticagrelor or DOACs.
Esophageal variceal ligation

Band ligation of esophageal varices is generally performed as an emergency treatment
for active upper variceal bleeding and, in this setting, measures for the management
of anticoagulants in urgent endoscopy should be applied. The band ligation can also
be performed as an elective procedure for primary prophylaxis of varices that have
never previously bleed. A case-control study showed an incidence of delayed
bleeding around 3.4%. In the same study, aspirin or anticoagulation were not
independently associated with the risk of bleeding, even though they were taken by a
small minority (1.3%) of patients[92].
No data regarding the risk of bleeding in patients taking other agents, such as
thienopyridines, ticagrelor or DOACs, is available.
Endoscopic retrograde cholangiopancreatography

The risk of bleeding during endoscopic retrograde cholangiopancreatography (ERCP)
is reported in about 0.1% to 2% of procedures with sphincterotomy[93].
In this regard, a meta-analysis showed that, even if sphincterotomy before stent
placement reduces the risk of post ERCP pancreatitis (OR = 0.34, 95%CI: 0.12-0.93, P =
0.04), it is associated with a higher risk of post-ERCP bleeding (OR = 9.70, 95%CI:
1.21-77.75, P = 0.03)[94].
Patient factors affecting the risk of bleeding after sphincterotomy include
anticoagulant therapy, presence of coagulopathies, and active cholangitis.
On the other side, procedural factors affecting the risk of bleeding are the
operator’s experience and the type of current used during the sphincterotomy. A
meta-analysis confirmed as a mixed-current was associated with a lower risk of
bleeding (12.2%-95%CI, 4.1%, 20.3%) compared to pure-cut current (37.3%-95%CI,
27.3%, 47.3%), with a similar risk of pancreatitis[95].
Another meta-analysis showed that, compared to sphincterotomy, endoscopic
papillary balloon dilatation was associated with a lower risk of bleeding (OR = 0.12,
95%CI: 0.04-0.34, P < 0.01), even if presented a significant higher incidence of
pancreatitis (OR = 2.79, 95%CI: 1.74-4.45, P < 0.0001)[96].
The risk of bleeding after sphincterotomy in patients taking antiplatelet agents is
not completely defined. Several studies did not find any significant additional risk of
bleeding in patients taking antiplatelet agents[93,97-100]. Besides, a retrospective study
showed a higher incidence of post-sphincterotomy bleeding in patients continuing
aspirin until the day of sphincterotomy, compared to patients that had never taken
aspirin (9.7% vs 3.9%, P = 0.01)[101].
No data from literature is currently available regarding the risk of bleeding after
biliary lithotripsy and cholangioscopy in patients taking APA or anticoagulants.
Endoscopic ultrasound with fine-needle aspiration

Endoscopic ultrasound (EUS) plus fine-needle aspiration (FNA) is performed for
diagnosis and locoregional staging of esophageal, gastric, rectal, and pancreatic
cancers. Although the procedure includes the puncture of the tissue, the reported
incidence of bleeding is low.
A large systematic review of 51 articles with a total of 10941 patients undergoing
endoscopic ultrasound with fine-needle aspiration (EUS-FNA), showed bleeding in
0.17% of procedures, and most bleeding complications occurred after FNA performed
on pancreatic lesions [102] . Moreover, a prospective controlled study assessed the
incidence of bleeding after 222 EUS-FNA procedures in patients undergoing
aspirin/NSAIDs and LMWH compared to patients didn't take these therapies.
Bleeding occurred in 0% (0/26), 33.3% (2/6) and 3.7% (7/190) of the patients in the
aspirin/NSAIDs, LMWH, and control groups, respectively (P = 0.023)[103]. This data
confirms as EUS-FNA is a safe procedure, even if performed in patients taking aspirin
or NSAIDs.
No data is available regarding the risk of bleeding after EUS-FNA in patients taking
anticoagulants.
Peroral endoscopic myotomy

Peroral endoscopic myotomy (POEM) is a new endoscopic technique for the

treatment of esophageal achalasia, with excellent results[104].

Since the view on the vasculature around the muscle fibers is optimal, and only a
few vessels are encountered in the submucosal tunnel, major bleeding is not frequent
during the procedure. In fact, according to a recent meta-analysis, massive
hemorrhage was reported in 0.2% of POEMs[105].
To date, no data on the risk of bleeding in patients taking antiplatelets or
anticoagulants is available.
MANAGEMENT OF ANTITHROMBOTIC AGENTS IN

ELECTIVE PROCEDURES
Current international practice guidelines provide a specific recommendation on the
management of anticoagulant therapy in the periendoscopic period.
The management of anticoagulants depends on the type of molecule, the estimated
risk of bleeding due to the endoscopic procedure, and the underlying thrombotic risk
deriving from cardiovascular disease.
With regard to the first parameter, ASGE, ESGE/BSG and APAGE/APSDE
guidelines identify specific risk groups (Table 1). The low-risk group includes all
endoscopic diagnostic procedures (including EGD, colonoscopy and enteroscopy with
or without mucosal biopsies, EUS without FNA) and ERCP. The high-risk group
includes polypectomy, EMR, ESD, therapeutic enteroscopy, ERCP with biliary or
pancreatic sphincterotomy, ampullectomy, EUS with FNA, dilatation of strictures and
PEG placement. These two groups are homogeneous between the guidelines, with the
exception of enteral stents that are still controversial and classified as low-risk by
ASGE and APAGE/APSDE, and as high-risk by ESGE/BSG. POEM is not classified
by any of the guidelines, but it could be ascribed to high-risk procedures. Moreover,
APAGE/APSDE consider a third group of ultra-high risk procedures, including ESD
and EMR of polyps > 2 cm, for which specific indications are provided.
On the other hand, the assessment of cardiovascular risk differs between the three
guidelines and is summarized in Table 2.
Aspirin and NSAIDs

With regards to aspirin, ASGE guidelines judge the use of low doses of aspirin and
NSAIDs safe and suggest to continue these drugs in the periendoscopic period[3].
On the other side, ESGE/BSG and APAGE/APSDE guidelines recommend
continuing aspirin therapy for almost all endoscopic procedures, with some
exceptions.
ESGE/BSG recommend aspirin discontinuation, on an individual basis, in patients
undergoing ESD, EMR for upper gastrointestinal lesions and colonic lesions > 2 cm,
and ampullectomy[4]. Besides, APAGE/APSDE recommend discontinuation of aspirin
in all patients undergoing ESD and EMR of all large (> 2 cm) polyps[5] (Figure 1).
Thienopyridines (clopidogrel, prasugrel, ticagrelor)

Recommendations on thienopyridines management are provided depending on the
estimate procedure risk:
(1) For patients undergoing low-risk endoscopic procedures, all guidelines
recommend continuing thienopyridine. Concerning dual antiplatelet therapy, ESGE
suggests continuing dual antiplatelet therapy, while APAGE/APSDE advice to don’t
stop both antiplatelet agents;
(2) For patients undergoing high-risk endoscopic procedures, ASGE and
ESGE/BSG recommend to assess before the cardiovascular risk (CVR, Table 2): If low
CVR, stop thienopyridine before endoscopy. In the case of dual APA therapy, both
ASGE and ESGE/BSG agree to continue aspirin if already prescribed; if high CVR,
ASGE recommends discontinuing thienopyridine at least 5 d before or switch to ASA,
while ESGE/BSG suggest considering discontinuation of thienopyridine 5 d before
only after 12 mo following insertion of drug-eluting coronary stent or after 1 mo after
insertion of a bare metal coronary stent.
APAGE/APSDE recommend discontinuing thienopyridine at least 5 d before
endoscopy in all patient undergoing a high-risk endoscopy procedure regardless of
the CVR.
With regard to patients with dual APA therapy, all guidelines agree to withhold
the thienopyridine and continue aspirin. Moreover, according to APAGE/APSDE
ultra-high risk procedures may require stopping both antiplatelet agents (Figure 2).
After the procedure, the suggested management differs according to the guidelines:
ASGE suggests to resume thienopyridine after the procedure once hemostasis is
achieved; in this setting, a loading dose of thienopyridine should be considered

Table 1 Stratification of endoscopic procedures based on the risk of bleeding according to international guidelines
Practice guidelines
Procedure risk group
ASGE[3] ESGE/BSG[4] APAGE/APSDE[5]
Low-risk (1) Diagnostic (EGD, colonoscopy, (1) Diagnostic procedures +/– (1) Diagnostic endoscopy with
flexible sigmoidoscopy) including biopsy; (2) Biliary or pancreatic biopsy; (2) Endoscopic ultrasound
mucosal biopsy; (2) ERCP with stent stenting; (3) Diagnostic EUS and (4) without fine needle aspiration; (3)
(biliary or pancreatic) placement or Device-assisted enteroscopy without ERCP with biliary or pancreatic
papillary balloon dilation without polypectomy stenting; (4) Diagnostic push or
sphincterotomy; (3) Push enteroscopy device-assisted enteroscopy; (5)
and diagnostic balloon-assisted Video capsule endoscopy; (6)
enteroscopy; (4) Capsule endoscopy; Oesophageal, enteral and colonic
(5) Enteral stent deployment stenting and (7) Argon plasma
(controversial); (6) EUS without FNA; coagulation
(7) Argon plasma coagulation and (8)
Barrett’s ablation
High-risk (1) Polypectomy; (2) Biliary or (1) Polypectomy; (2) ERCP with (1) Polypectomy; (2) ERCP with
pancreatic sphincterotomy; (3) sphincterotomy; (3) Ampullectomy; sphincterotomy ± balloon
Treatment of varices; (4) PEG/PEJ (4) EMR; (5) ESD; (6) Dilation of sphincteroplasty; (3) Dilatation of
placement; (5) Therapeutic balloon- strictures; (7) Therapy of varices; (8) strictures; (4) Injection or banding of
assisted enteroscopy; (6) EUS with PEG; (9) EUS with FNA and (10) varices; (5) PEG/PEJ placement; (6)
FNA; (7) Endoscopic hemostasis; (8) Oesophageal, enteral or colonic EUS with FNA and (7)
Tumor ablation; (9) Cystgastrostomy; stenting Ampullectomy
(10) Ampullary resection; (11) EMR;
(12) Endoscopic submucosal
dissection and (13) Pneumatic or
bougie dilation
Ultra-high-risk NA NA (1) ESD; (2) EMR of large (> 2 cm)
polyps
ASGE: American society for gastrointestinal endoscopy; ESGE/BSG: European society of gastrointestinal endoscopy and British society of
gastroenterology; APAGE/APSDE: Asian pacific association of gastroenterology and Asian pacific society for digestive endoscopy; EGD:
Esophagogastroduodenoscopy; EUS: Endoscopic ultrasound; FNA: Fine-needle aspiration; ERCP: Endoscopic retrograde cholangiopancreatography; PEG:
Percutaneous endoscopic gastrostomy; PEJ: Percutaneous endoscopic jejunostomy; EMR: Endoscopic mucosal resection; ESD: Endoscopic submucosal
dissection; NA: Not assessed.
among patients at risk for thrombosis[3]; ESGE/BSG recommend that thienopyridine

should be resumed up to 48 h after the procedure depending on the perceived
bleeding and thrombotic risks[4]; APAGE/APSDE recommend early resumption of
thienopyridine within 5 d after endoscopic hemostasis in patients with drug-eluting
coronary stents[5].
Warfarin
Also for warfarin, recommendations are provided depending on the estimate
procedure risk:
(1) For patients undergoing low-risk endoscopic procedures, all guidelines
recommend continuing warfarin. In addition, ESGE/BSG and APAGE/APSDE
suggest to check the INR the week before endoscopy to ensure it is in the normal
range[4,5];
(2) For patients undergoing high or ultra-risk endoscopic procedures, all guidelines
recommend to assess before the CVR (Table 2): If low CVR, discontinue warfarin 5 d
before the procedure and check the INR before the procedure to ensure values < 1.5
according to ESGE/BSG [ 4 ] or less conservative values < 2 according to
APAGE/APSDE[5]; if high CVR, discontinue warfarin 5 d before the procedure and
administer bridge therapy with LMWH. In addition, ESGE/BSG recommend
withdrawing the last dose of LMWH more than 24 h before the procedure[4] (Figure 3).
All guidelines recommend resuming warfarin the same day/evening of the
procedure after proper hemostasis has been achieved. Moreover, for patients with
high CVR, ESGE/BSG and APAGE/APSDE specify to continue LMWH until
therapeutic INR range has been achieved.
DOACs (dabigatran, rivaroxaban, apixaban, edoxaban)

For patients undergoing low-risk endoscopic procedures, ASGE and APAGE/APSDE
recommend continuing DOACs in the periendoscopic period, similar to what is
suggested for warfarin [3,5] . On the contrary, ESGE/BSG guidelines recommend
omitting the DOACs dose the morning of the procedure. Nevertheless, this last
statement is reported as a weak recommendation and supported by very low-quality
evidence[4].

Table 2 Stratification of thrombotic risk according to international guidelines
Practice guidelines
Thrombotic risk category
ASGE[3] ESGE/BSG[4] APAGE/APSDE[5]
Low-risk Anticoagulant therapy: (1) Bileaflet Antithrombotic therapy: (1) Antithrombotic therapy: (1) Acute
aortic valve prosthesis without AF Ischaemic heart disease without coronary syndrome or percutaneous
and no other risk factors for CVA; (2) coronary stent; (2) Cerbrovascular coronary intervention > 6 mo ago;
VTE > 12 mo previous and no other disease; and (3) Peripheral vascular and (2) Stable coronary artery
risk factors; and (3) Atrial fibrillation disease. disease.
with CHA2DS2-VASc score < 2
Anticoagulant therapy: (1) Prosthetic Anticoagulant therapy: (1) Non-
metal heart valve in aortic position; valvular atrial fibrillation with a
(2) Xenograft heart valve; (3) Atrial CHA2DS2-VASc score ≤ 5; (2)
fibrillation without valvular disease; Prosthetic valve without atrial
(4) > 3 mo after venous fibrillation; and (3) > 3 mo after
thromboembolism; and (5) venous thromboembolism
Thrombophilia syndromes
Moderate-risk Anticoagulant therapy: (1) Bileaflet
aortic valve prosthesis and one or
more of the following risk factors:
AF, prior CVA or TIA, hypertension,
diabetes, congestive heart failure, age
> 75 yr; (2) VTE within the past 3-12
monon-severe thrombophilia
(heterozygous factor V Leiden or
prothrombin gene mutation); and (3)
Recurrent VTEactive cancer (treated
within 6 mo or palliative)
High-risk Anticoagulant therapy: (1) Any Antithrombotic therapy: (1) Drug Antithrombotic therapy: (1) Acute
mitral valve prosthesis; (2) Any eluting coronary artery stents within coronary syndrome or percutaneous
caged-ball or tilting disc aortic valve 12 mo of placement; and (2) Bare coronary intervention 6 wk–6 mo.
prosthesis; (3) Recent (within 6 mo) metal coronary artery stents within 1
Anticoagulant therapy: (1) Non-
CVA or TIA; and (4) Atrial fibrillation mo of placement.
valvular atrial fibrillation with a
with CHA2DS2-VASc score ≥ 2
Anticoagulant therapy: (1) Prosthetic CHA2DS2-VASc score > 5; (2)
metal heart valve in mitral position; Metallic mitral valve; (3) Prosthetic
(2) Prosthetic heart valve and atrial valve with atrial fibrillation; (4) < 3
fibrillation; (3) Atrial fibrillation and mo after venous thromboembolism;
mitral stenosis; and (4) < 3 mo after and (5) Severe thrombophilia (protein
venous thromboembolism C or protein S deficiency and (6)
antiphospholipid syndrome)
Very high-risk Antithrombotic therapy: Acute
coronary syndrome or percutaneous
coronary intervention < 6 wk
ASGE: American society for gastrointestinal endoscopy; ESGE/BSG: European society of gastrointestinal endoscopy and British society of
gastroenterology; APAGE/APSDE: Asian pacific association of gastroenterology and Asian pacific society for digestive endoscopy; AF: Atrial fibrillation;
CVA: Cerebrovascular accident; VTE: Venous thromboembolism; TIA: Transient ischemic attack.
For patients undergoing high-risk endoscopic procedures, all guidelines

recommend discontinuing DOACs before endoscopy for the appropriate drug-specific
interval, adjusting for creatinine clearance [3-5] . In this regard, ESGE/BSG and
APAGE/APSDE specify to take the last dose of DOACs ≥ 48 h before the procedure[4,5]
(Figure 4).
Unlike reintroduction of warfarin, which results in delayed anticoagulation for
several days, a therapeutic intensity of anticoagulation is restored within 3 h of taking
a therapeutic dose of a DOAC. Because of the high-risk of bleeding associated with
the therapeutic intensity of anticoagulation after an invasive procedure, guidelines
suggest a delay in reintroducing DOACs after a high-risk procedure. This delay will
depend on the bleeding risk associated with the procedure and will usually be 24-48
h[4]. For procedures with a significant risk of delayed bleeding such as EMR or ESD, a
longer period of discontinuation may be considered for patients with a relatively low-
thrombotic risk.
According to ASGE guidelines, if DOACs cannot be restarted within 24 h after a
high-risk procedure because of concern regarding the adequate hemostasis due to
their short onset of action, then thromboprophylaxis (e.g., LMWH bridge) should be
considered for patients at high-risk for thromboembolism[3].
On the contrary, APAGE/APSDE recommends early resumption of DOACs soon
after the procedure after adequate hemostasis has been achieved.

Figure 1
Figure 1 Management of aspirin and nonsteroidal anti-inflammatory drugs in elective endoscopic procedures according to international guidelines.
NSAID: Nonsteroidal anti-inflammatory drugs; ASGE: American society for gastrointestinal endoscopy; ESGE/BSG: European society of gastrointestinal endoscopy
and British society of gastroenterology; APAGE/APSDE: Asian pacific association of gastroenterology and Asian pacific society for digestive endoscopy; EMR:
Endoscopic mucosal resection; ESD: Endoscopic submucosal dissection.
MANAGEMENT OF ANTITHROMBOTIC AGENTS IN

URGENT PROCEDURES
Antiplatelets agents
ASGE guidelines recommend consultation with the prescribing specialist before
stopping APAs during gastrointestinal bleeding in patients for which the
cardiovascular risk overcomes the potential consequences of bleeding, namely
patients with: (1) Placed drug eluting intracoronary stents within 1 year, AND (2)
Insertion of a bare metal intracoronary stent within 1 mo, or after an acute coronary
syndrome within 90 d[3].
The ESGE/BSG guidelines propose an algorithm in which patient management
depend from primary or secondary prophylaxis.
The algorithm recommends withholding aspirin until the third day after
endoscopic treatment of high-risk stigmata in patients taking APA for secondary
prophylaxis[4].
In this regards, two studies have shown that in patients taking low-dose aspirin for
secondary cardiovascular prophylaxis, the all-cause mortality was lower if aspirin
was continued[106,107].
Besides, APAGE/APSDE guidelines recommend withholding aspirin only in
patients with serious or life-threatening bleeding in places where endoscopy is not
readily available[5].
With regard to patients taking dual antiplatelet therapy having acute
gastrointestinal bleeding, both ESGE/BSG and APAGE/APSDE recommend
continuation of aspirin and withholding clopidogrel. In these patients, resumption of
therapy preferably within 5 d after endoscopic hemostasis is recommended by
APAGE/APSDE guidelines, whereas ESGE/BSG and ASGE suggest consulting with a
cardiologist for the management after urgent endoscopic treatment.
Warfarin
The estimated incidence of gastrointestinal bleeding in patients in anticoagulant
therapy ranges between 1%-4% per year[108].
The management of patients using anticoagulants with active gastrointestinal
bleeding has been the focus of numerous studies for many years.
The ESGE/BSG and ASGE guidelines recommend to stop the therapy and correct

Figure 2
Figure 2 Management of thienopyridines in elective endoscopic procedures according to international guidelines. ASGE: American society for
gastrointestinal endoscopy; ESGE/BSG: European society of gastrointestinal endoscopy and British society of gastroenterology; APAGE/APSDE: Asian pacific
association of gastroenterology and Asian pacific society for digestive endoscopy; APA: Antiplatelet agents; ASA*: Acetylsalicylic acid.
the INR in patients taking vitamin K antagonists with signs of severe bleeding, before
performing urgent endoscopy[109-111]. Moreover, they also recommend not to delay
endoscopy if INR < 2.5. In this regard, Choudari and colleagues described a
retrospective series of 52 patients which developed bleeding while taking warfarin.
The outcome and the endoscopy efficacy in patients with an INR corrected between
1.5 and 2.5 were good and similar to those recorded in patients not taking
anticoagulants. Therefore, even a partial correction of the INR seems to be associated
with a good outcome[112].
In a retrospective cohort study of 233 consecutive anticoagulated patients
undergoing urgent endoscopy with successful hemostasis, 95% of them had an INR
between 1.3 and 2.7. The rate of re-bleeding was 23%, but INR was not a predictor of
re-bleeding on multivariable analyzes[113].
Another retrospective study of patients taking warfarin at the moment of
admission for gastrointestinal bleeding, reports 55 patients with INR value of 4.0 or
greater (supratherapeutic) and 43 with INR in the range 2.0 to 3.9. Patients with
supratherapeutic INRs were more likely to have a gastrointestinal pathology
supporting the need of endoscopic evaluation, but no differences in the rate of re-
bleeding were recorded[114].
A large systematic review of 1869 patients with nonvariceal upper GI bleeding,
showed that INR value at the initial presentation of the event did not predict the risk
of re-bleeding. Rather, the finding of INR > 1.5 during non-variceal digestive
hemorrhage was associated with an increase in mortality after correction in patients
with specific comorbidities. Hence, in this study, the INR value was found to be
useful in the risk stratification than as a predictor of re-bleeding[115]. Furthermore, in a
retrospective case-control study, Irwin and colleagues have highlighted that patients
with supratherapeutic INR at the time of gastrointestinal bleeding had a lower
mortality rate 30 d after the event compared to patients not taking warfarin[116].
This evidence suggests that the strategy aimed to normalize the INR in all patients
delaying the timing of endoscopy could not be so useful in the clinical practice.
Hence, as suggested by ASGE and ESGE/BSG practice guidelines, the endoscopic
treatment can be considered effective and relatively safe with INR values < 2.5[3,4].

Figure 3
Figure 3 Management of warfarin in elective endoscopic procedures according to international guidelines. ASGE: American society for gastrointestinal
endoscopy; ESGE/BSG: European society of gastrointestinal endoscopy and British society of gastroenterology; APAGE/APSDE: Asian pacific association of
gastroenterology and Asian pacific society for digestive endoscopy; INR: International Normalized Ratio; LMWH: Low molecular weight heparin.
In the management of a patient with active gastrointestinal bleeding, the decision to

correct the coagulopathy it’s often difficult because of the risk of thromboembolic
consequences.
The thrombotic risk after transient withdrawal of anticoagulant therapy in acute
gastrointestinal bleeding settings was explored by 2 small studies conducted on 27
and 28 patients. The withdrawal time was variable between 5 and 14 d, in one of the
two studies it was also administered vitamin K or frozen plasma was given to 7
patients to reverse anticoagulation. Both studies showed a low-risk of thrombotic
complications[117,118].
All the guidelines (ASGE, ESGE/BSG and APAGE/APSDE) agree on the urgent
anticoagulation reversal in all patients presenting with life-threatening
gastrointestinal bleeding, regardless of therapeutic or supra-therapeutic INR
elevations[3-5,119].
Specifically, ESGE/BSG recommend estimating the cardiovascular risk of the
patient by consulting with a cardiologist before starting INR correction[4].
For patients without signs of active bleeding and hemodynamically stable, the
usefulness of INR correction should be evaluated on a case by case basis.
For an urgent correction of coagulopathy in patients taking warfarin, ASGE and
ESGE/BSG guidelines suggest the administration of prothrombin complex
concentrates (PCC) or fresh frozen plasma (FFP)[3,4].
Moreover, ESGE/BSG highlight that it is preferable to use PCC in combination
with intravenous vitamin K at the dosage of 5-10 mg K to prevent “rebound
coagulopathy” limiting the use of FFP when PCC is not available[4].
Other guidelines, such as those of the APAGE/APSDE recommend only the
combination of PCC with concomitant low-dose vitamin K (< 5 mg instead of 5-10
mg) administration [5] . With regard to the latter, the decision to prefer low-dose
vitamin K is based on the evidence from four randomized clinical trials that the
optimal dose of vitamin K to achieve a normalization of the INR value ranges
between 1 and 2.5 mg[120-123].
Currently, there are no randomized clinical trials comparing prothrombin PCC and

Figure 4
Figure 4 Management of direct oral anticoagulants in elective endoscopic procedures according to international guidelines. ASGE: American society for
gastrointestinal endoscopy; ESGE/BSG: European society of gastrointestinal endoscopy and British society of gastroenterology; APAGE/APSDE: Asian pacific
association of gastroenterology and Asian pacific society for digestive endoscopy; DOAC: Direct oral anticoagulant.
FFP for warfarin reversal in acute GI bleeding.

In 2014 Karaca et al[124] performed a prospective, non-randomized, comparative
study of 40 patients taking warfarin with upper gastrointestinal haemorrhage and
INR > 2.1. Patients received either PCC or FFP, and INR levels were reversed more
quickly in PCC group at the second and sixth h (second h INR: 1.53 vs 4.50, P < 0.01,
sixth h INR: 1.52 vs 2.41, P < 0.01). At the time of endoscopy, no patient in the PCC
group had active bleeding compared with 7 in the FFP group (0% vs 35 %, P < 0.01).
Concerning the thrombotic risk, a meta-analysis of 2011 showed a similar risk for
the two agents (~ 1%)[125].
In addition to a faster onset of action, in the clinical practice, PCC have other
advantages, as no need for ABO matching, less risk for volume overload because of
smaller transfusion volume and minimal risk of infectious transmission. On the
contrary, a disadvantage is represented by the higher cost[126].
With regard to the resumption of warfarin after the bleeding event, APAGE-
APSDE guidelines recommend resuming warfarin by day 3 after adequate hemostasis
is achieved and to consider bridge with LMWH in patients with high thrombotic
risk[5]. On the other side, ESGE/BSG suggest resuming warfarin between 7 and 15 d
following the bleeding event if hemostasis is successfully achieved[4].
DOACs
The ESGE/BSG guidelines recommend the use of platelet transfusion or
desmopressin for more severe bleeding, although, there is no clear evidence to
support this approach [4] . As evidenced by recent data, platelet transfusion is
associated with an increase in mortality[127].
The most recent endoscopic APAGE/APSDE guidelines, do not recommend
making specific assays to estimate the anticoagulant activity of DOACs in acute
bleeding[5]. Prothrombin time and activated partial thromboplastin time could be
inaccurate in DOACs activity evaluation and currently specific assays are not
routinely available.
With the exception of patients with reduced renal clearance, generally, the best
strategy in patients taking DOACs is their withdrawal due to their short half-lives.
Moreover, it should also be considered that, to date, antidotes and direct inhibitor
of DOACs are available. In a multicenter open-label study of 503 patients,
idarucizumab proved to be safe and effective in neutralizing the anticoagulant effect
of dabigatran in emergency situations[15].
Another study assessed the effectiveness of andexanet alfa, a modified recombinant

inactive form of human factor Xa, for bleeding associated with Factor Xa Inhibitors
such as rivaroxaban, apixaban and edoxaban. The study showed that treatment with
andexanet in patients with major acute bleeding associated with the use of a factor Xa
inhibitor, markedly reduced anti-factor Xa activity, with an excellent or good
hemostatic efficacy in 82% of patients[16].
After index bleeding episode, APAGE/APSDE recommend resuming DOACs by
day 3 after hemostasis is successfully achieved, without heparin bridging[5].
On the contrary, ASGE and ESGE/BSG guidelines do not provide a specific
recommendation on the resumption of DOACs[3,4].
CONCLUSIONS
Currently, there is sufficient evidence from the literature to assess the basal risk of
bleeding associated with main endoscopic procedures in patients who do not take
antithrombotic agents.
On the contrary, there are not sufficient data allowing to evaluate as this risk
increases in patients taking anticoagulants, especially in some specific procedures (e.g.
endoscopic dilatation, stenting, esophageal variceal ligation, EUS-FNA etc).
Nevertheless, the high-risk associated with these procedures makes further studies
unlikely to be carried out in the future.
To date, current international practice guidelines provide specific
recommendations for the management of anticoagulants in endoscopy, with a good
agreement and some major differences that have already been discussed (Figures 1-4).
Some of these differences may be explained by a different proposed approach,
different geographical area of reference and different year of publication.
Nevertheless, even with some discrepancy, guidelines only represent the guide for
a common policy, over which a tailored approach should always be applied. On this
line, the assessment of the individual risk-benefit ratio is essential.
As a matter of fact, the interruption of anticoagulants is undoubtful effective in
reducing the risk of bleeding during endoscopic procedures. Despite this, the
thromboembolic risk that follows the therapy suspension should not be
underestimated. For this reason, the individual decision should be taken on a case by
case basis taking into account every single factor.
In addition, since several endoscopic examinations are commonly requested by the
general practitioners or by other consultants as “open access”, a preliminary
gastroenterological visit with the patient is essential to better assess the procedure risk
and the proper schedule for withdrawal of anticoagulants, as well as written
information on their resumption, should be provided at discharge.
Moreover, when necessary, consultation with the cardiologist or the hematologist
has primary importance for a tailored approach on the single patient.
In the future, further studies are needed to clarify better the grey areas and topics
on which the guidelines still present some controversial points. In the meantime, we
suggest to comply with the international guidelines strictly and to discuss difficult
decisions within multidisciplinary boards.
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ISSN 1948-5190 (online)

World J Gastrointest Endosc 2020 June 16; 12(6): 172-197

Published by Baishideng Publishing Group Inc

WJGE https://www.wjgnet.com I June 16, 2020 Volume 12 Issue 6

ABOUT COVER Editorial Board Member of World Journal of Gastrointestinal Endoscopy,

Responsible Electronic Editor: Mei-Yi Liu

NAME OF JOURNAL INSTRUCTIONS TO AUTHORS

ISSN GUIDELINES FOR ETHICS DOCUMENTS

LAUNCH DATE GUIDELINES FOR NON-NATIVE SPEAKERS OF ENGLISH

FREQUENCY PUBLICATION ETHICS

EDITORS-IN-CHIEF PUBLICATION MISCONDUCT

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PUBLICATION DATE STEPS FOR SUBMITTING MANUSCRIPTS

COPYRIGHT ONLINE SUBMISSION

WJGE https://www.wjgnet.com II June 16, 2020 Volume 12 Issue 6

DOI: 10.4253/wjge.v12.i6.172 ISSN 1948-5190 (online)

Management of antiplatelet or anticoagulant therapy in endoscopy:

WJGE https://www.wjgnet.com 172 June 16, 2020 Volume 12 Issue 6

and license their derivative works procedures.

WJGE https://www.wjgnet.com 173 June 16, 2020 Volume 12 Issue 6

ticlopidine, clopidogrel and the most recent third-generation thienopyridine agents

RISK OF BLEEDING ASSOCIATED WITH ENDOSCOPIC

WJGE https://www.wjgnet.com 174 June 16, 2020 Volume 12 Issue 6

sigmoidoscopy, including mucosal biopsy, present a low-risk of procedural bleeding,

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Endoscopic mucosal resection

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Endoscopic submucosal dissection

Percutaneous endoscopic gastrostomy

WJGE https://www.wjgnet.com 177 June 16, 2020 Volume 12 Issue 6

Esophageal variceal ligation

Endoscopic retrograde cholangiopancreatography

Endoscopic ultrasound with fine-needle aspiration

Peroral endoscopic myotomy

WJGE https://www.wjgnet.com 178 June 16, 2020 Volume 12 Issue 6

treatment of esophageal achalasia, with excellent results[104].

MANAGEMENT OF ANTITHROMBOTIC AGENTS IN

Aspirin and NSAIDs

Thienopyridines (clopidogrel, prasugrel, ticagrelor)

WJGE https://www.wjgnet.com 179 June 16, 2020 Volume 12 Issue 6

among patients at risk for thrombosis[3]; ESGE/BSG recommend that thienopyridine

DOACs (dabigatran, rivaroxaban, apixaban, edoxaban)

WJGE https://www.wjgnet.com 180 June 16, 2020 Volume 12 Issue 6

Table 2 Stratification of thrombotic risk according to international guidelines

For patients undergoing high-risk endoscopic procedures, all guidelines

WJGE https://www.wjgnet.com 181 June 16, 2020 Volume 12 Issue 6

MANAGEMENT OF ANTITHROMBOTIC AGENTS IN

WJGE https://www.wjgnet.com 182 June 16, 2020 Volume 12 Issue 6

WJGE https://www.wjgnet.com 183 June 16, 2020 Volume 12 Issue 6

In the management of a patient with active gastrointestinal bleeding, the decision to

WJGE https://www.wjgnet.com 184 June 16, 2020 Volume 12 Issue 6

FFP for warfarin reversal in acute GI bleeding.

WJGE https://www.wjgnet.com 185 June 16, 2020 Volume 12 Issue 6

WJGE https://www.wjgnet.com 186 June 16, 2020 Volume 12 Issue 6

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50 Albéniz E, Gimeno-García AZ, Fraile M, Ibáñez B, Guarner-Argente C, Alonso-Aguirre P, Álvarez MA,

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72 Terasaki M, Tanaka S, Shigita K, Asayama N, Nishiyama S, Hayashi N, Nakadoi K, Oka S, Chayama K.