Shinshu M ed J, 60⑶ :143〜148, 2012

Assessment of Safety of Using Antithrombotic Agents during
Esophagogastroduodenoscopy:Rationale and Design of the ASAMA Study
Hiroki KASAI ＊ , Tomoaki SUGA , Uichi IKEDA , Jiro YOSHIOKA
Eiji TANAKA , Taiji AKAMATSU , for the ASAMA study Investigators
1) Department of Cardiovascular Medicine, Shinshu University School of Medicine
2) Department of Gastroenterology, Shinshu University School of Medicine
3) Nagano Red Cross Hospital
4) Nagano Prefectural Suzaka Hospital

Background :Guidelines for the management of anticoagulation and antiplatelet therapy during endoscopic
procedures have been established by the Japanese Circulation Society and the Japan GastroenterologicalEndoscopy Society. However, these Japanese guidelines are not in accordance with those of the American
Society for Gastrointestinal Endoscopy(ASGE).The ASGE guidelines indicate that aspirin and warfarin may
be continued for endoscopic procedures associated with a low risk of bleeding. In contrast, the Japaneseguidelines recommend cessation of antithrombotic agents before endoscopy,even if the procedure is classiﬁed
as low risk.In this trial,we investigate the feasibility of performing esophagogastroduodenoscopy(EGD)withbiopsy without the cessation of antithrombotic agents in Japanese patients, in accordance with the ASGE
guidelines.
Methods and Results:This investigation is a prospective,non‑randomized,multicenter trial of patients who
undergo scheduled EGD with biopsy while under antithrombotic therapy.Patients will either continue to takeantithrombotic agents (group A)or discontinue their use (group B).Control subjects not under antithrombotic
therapy will also be recruited (group C). The primary endpoint is gastrointestinal hemorrhage and thesecondary endpoint is a cardiovascular event.
Summary:This is the ﬁrst multicenter trial in Japan to investigate the safety of continuing antithrombotic
therapy during EGD with biopsy. Shinshu Med J 60 : 143 ―148, 2012
(Received for publication November 10, 2011;accepted in revised form January 23, 2012)
Key words:thrombosis, platelet inhibitors, aspirin, anticoagulants, endoscopic procedure

Introduction

copy is a common clinical consideration. The decision is challenging because the risk of a thrombotic

Evidence has accumulated to support the use of

event during the interruption of therapy must be

anticoagulants and antiplatelet agents for the pre-balanced carefully against the risk of bleeding whenvention of cardio‑ and cerebrovascular diseases.

treatment is resumed.

The periprocedural management of patients who

In deciding whether to temporarily discontinue

might require temporary interruption of these

antithrombotics during a procedure,it is important

agents to undergo diagnostic and therapeutic endos-

to assess the inherent risk of bleeding associatedCorresponding author:Hiroki Kasai

with that speciﬁc procedure. The risk varies with

Department of Cardiovascular Medicine,Shinshu Univer-procedure type and depends on whether or notsity School of Medicine,3‑1‑1 Asahi,M atsumoto,Nagano
390‑8621 Japan

therapeutic interventions are performed.It is gener-

Hiroki Kasai and Tomoaki Suga contributed equally toally accepted that all diagnostic procedures with or

this work.

without mucosal biopsy,as well as endoscopic retro-

No. 3, 2012143

Kasai.Suga.Ikeda et al.

grade cholangiopancreatography without sphincter-

antagonists signiﬁcantly increases the risk of gas-otomy,diagnostic balloon‑assisted enteroscopy,and

trointestinal bleeding when compared with monoth-endosonography without tissue sampling, are low‑erapyrisk procedures .Procedures with an increased risk

administration of clopidogrel in addition to aspirinof bleeding include endoscopic polypectomy or en-increases the relative risk of gastrointestinal bleed-doscopic mucosal resection, laser ablation, thera-ing by up to 70% .Therefore,in patients who takepeutic balloon‑assisted enteroscopy,and endoscopic

clopidogrel plus aspirin,the bleeding risk will likely

sphincterotomy.These therapeutic procedures havebe reduced by stopping clopidogrel and continuing

the potential to cause bleeding that is inaccessible

aspirin before an elective endoscopy.

or uncontrollable by endoscopic means.

and impairs the healing of ulcers . The

In 2005,the Japan Gastroenterological Endoscopy

Clinical evidence suggests that the continued

Society (JGES) established Japanese guidelines foradministration of warfarin during the periendos-

the management of anticoagulants and antiplatelet

copic period carries a low risk of bleeding in low‑

agents during endoscopic procedures .According torisk procedures .In a retrospective study,Gerson etthis recommendation, patients at low risk for aal. found that in 171 low‑risk procedures (upper

thromboembolic event should discontinue the use

endoscopy and colonoscopy, including the use ofof antithrombotics or anti‑platelet agents before amucosal biopsy)in patients taking therapeutic doses

low‑risk procedure as follows:warfarin,3‑4 days;of warfarin, no bleeding was clinically evident .

aspirin, 3 days;and ticlopidine,5 days.The recom-

Aspirin has been shown to prolong bleeding times

mendations of the Japanese Circulation Society

to up to 48 hours after ingestion . Two previous(2009)are similar to those of the JGES .There arestudies have demonstrated that aspirin is not as-

discrepancies between Japanese and Americansociated with an increased risk of post‑endoscopy

guidelines, even though the JGES guidelines were

bleeding. Furthermore, current studies suggest

established using the American Society for Gastro-that aspirin administration in the periendoscopic

intestinal Endoscopy (ASGE) guidelines as a refer-period is safe, even after high‑risk endoscopic pro-ence. The recommendations for management for

cedures such as polypectomyor sphincterotomy .

each category by a combination of procedural risks

Another antiplatelet agent, clopidogrel, causes

and thrombotic risks diﬀer between ASGE andirreversible platelet inhibition.Upon drug cessation,

JGES.Speciﬁcally,the ASGE guidelines recommend

a minimum of 5 days is required for platelet aggre-that aspirin and warfarin be continued for endos-

gation to return to 50% of normal. The publishedcopic procedures with a low risk of inducing bleed-data do not provide an accurate gauge for determin-

ing.This ASGE recommendation regarding continu-

ing the risk of bleeding associated with clopidogrel

ing antithrombotic agents during the periendoscopic(or ticlopidine)after an endoscopic procedure. Cur-

period is based on the clinical data about bleeding

rent guidelines recommend withholding clopidogrelrisk reported by Gerson and on the fact that there

for at least 7 days before a high‑risk endoscopic

are no clinical trials demonstrating an increased

procedure . Patients at high risk for a cardiovas-

incidence of bleeding in patients who have under-

cular event, particularly stent thrombosis, shouldgone upper endoscopy with biopsy while taking

defer elective endoscopic procedures until clopido-

antithrombotic agents.In contrast,the JGES guide-

grel can be safely discontinued .

lines recommend cessation of aspirin and warfarin

In patients taking both aspirin and clopidogrel,

before endoscopy,even if the procedure is classiﬁed

the risk of bleeding after an endoscopic procedure

as low risk. However the JGES guidelines have no

has not been determined. However, the eﬀects ofJapanese epidemiologic data about gastrointestinal

this drug combination on the gastrointestinal tract

bleeding after biopsy procedure without discontinu-

have been studied. The combined use of 2 platelet

ation of antithrombotic agent as a reference.About

144

Shinshu Med J Vol.60

Antithrombotic agents for endoscopic procedures

discontinuation of aspirin,the JGES guidelines referconsiderable amount of time, even when the endos-

to one report that bleeding time and bleeding vol-copic procedures are classiﬁed as low risk.

ume were normalized 3 days after cessation in 11

The actual risk of post‑endoscopic bleeding as-

healthy men . In the case of warfarin, the guide-sociated with taking antithrombotic agents is un-lines do not mention the length of discontinuation

known in Japanese patients. In this trial, we willwith reference to the risk of bleeding. Racialinvestigate the feasibility of performing EGD with

diﬀerences in susceptibility to bleeding and manifes-

biopsy without the cessation of antithrombotic

tations of thromboembolism may lead to diﬀerent

agents in Japanese patients,in accordance with therecommendations by diﬀerent countries .

ASGE guidelines.

On the other hand, Ono et al. performed a retrospective analysis of the management

Methodsofanticoagulants and antiplatelet agents for scheduled
endoscopy in Japanese patients. Among 8921

Objective
The Assessment of Safety of using Antithrom-patients who underwent scheduled endoscopy, 1383

botic Agents during

patients (15.5%) were receiving anticoagulants or(ASAMA) study is a prospective, non‑randomized,

antiplatelet agents .Of the 556 patients who under-

multicenter study to investigate the feasibility ofwent endoscopy without cessation of these medica-

continuing antithrombotic agents during EGD with

tions, 41 (7.4%) underwent invasive procedures,

biopsy.

including endoscopic mucosal resection.No complications related to bleeding were observed in thesepatients.

endoscopic procedures

Study Population
Patients who will undergo scheduled EGD with orwithout biopsy and are receiving warfarin or anti-

performed a survey on theplatelet agents［aspirin, thienopyridines (clopido-

management of antithrombotic therapy for endos-

grel or ticlopidine)］will be candidates to be

copic procedures. Participants comprised 13 endos-

enrolled (Fig.1).The patients will be divided into 2

copists from 13 hospitals in the Tokyo area.Threegroups, and will either continue antithrombotic

endoscopists (23%) reported having patients who

agents (group A)or discontinue these agents (groupexperienced thromboembolic events during the dis-

B).All the patients will be informed of the risks andcontinuation of anticoagulants or antiplatelet

beneﬁts of continuing or discontinuing antithrom-

agents for endoscopy. In contrast, no endoscopists

botic agents. Patients will be divided into candi-

reported having patients with severe bleeding due todates for group A or B at their own request andcontinuation of antithrombotic therapy during eso-

written informed consent will be obtained.In groupphagogastroduodenoscopy (EGD)with biopsy.

A, patients who normally take only 1 antithrom-

Fujishiro et al.

Thus the continued administration of antithrom-

botic agent will continue taking their medication as

botic agents during EGD with biopsy is quite likely

usual. Those who are taking clopidogrel or ti-

to be acceptable also in Japan.

clopidine in combination with aspirin will stop the

EGD is a common endoscopic procedure, andclopidogrel or ticlopidine 7 days before the proce-

EGD with biopsy is considered to be a low‑riskdure.Patients who are taking both warfarin and anprocedure byboth Japanese and Western guidelines.

antiplatelet agent will discontinue the use of either

If the procedure is classiﬁed as a low‑risk proce-

1 of the 2 drugs;the drug to be discontinued will be

dure, then the risk of hemorrhage is low. The

chosen at the discretion of each patientʼs attending

continued administration of antithrombotic agentsphysician.These protocols of continuing antithrom-

during EGD with biopsy is thus acceptable bybotic agents in group A are in accordance with

Western guidelines.In contrast,Japanese guidelines

ASGE guidelines.In group B,antithrombotic agentsrecommend stopping antithrombotic agents for awill be discontinued according to the guidelines of

No. 3, 2012145

Kasai.Suga.Ikeda et al.

Fig. 1 ASAMA study design. EGD ;esophagogastroduodenoscopy

JGES. Patients not under antithrombotic therapy

The primary endpoint is the occurrence of gastro-

will also be candidates to be enrolled (group C).The

intestinal hemorrhagic events requiring any treat-

decision whether to perform biopsy or not depends

ment. The secondary endpoint is a cardiovascularon the endoscopist. Among these candidates, theevent during the periprocedural period.The percent-patients who receive biopsy at the time of EGD will

age of endpoints will be compared between the 3

be eventually enrolled in this study (Group A,B,orgroups.

C).Patients with active gastrointestinal bleeding at

Discussion

the time of EGD before biopsy will be excluded
from the study. Five hundred subjects will beenrolled in each group.

There is little consensus in our daily practice
regarding the management of anticoagulation andOther exclusion criteria include the use of antith-antiplatelet therapyfor endoscopic procedures,evenrombotic agents other than aspirin and thienopyr-

after the establishment of the Japanese guidelines.

idines,the presence of drug‑eluting stents implanted

The ASAM A study is the ﬁrst prospective

within 1 year of the EGD procedure,a poor interna-

multicenter trial to investigate the safety oftional normalized ratio (INR＞3.0) within 1 monthcontinuing antithrombotic agents during electiveof the procedure, the presence of a bleeding dis-

EGD with biopsy in Japanese patients.

order, and pregnancy. Patients will be recruited

This trial is non‑randomized because todayʼsfrom 18 participating sites in Nagano prefecture in

JGES guidelines recommend the cessation of antith-

Japan and will be enrolled from M arch 2011 torombotic agents before endoscopy. All the patients

March 2014.

will be enrolled into group A or B at their own

The protocol has been reviewed and approved

request,after receiving information on the risks andby each participating siteʼs ethics committee. The

beneﬁts of continuing or discontinuing antithrom-

trial has been registered at the University

botic agents. If the frequency of gastrointestinal

Hospital M edical Information Network (UMIN)

hemorrhagic events is identical among the three(ID000004937).

groups,a further randomized controlled trial will be

Study Endpoints
146

needed.
Shinshu Med J Vol.60

Antithrombotic agents for endoscopic proceduresThis trial addresses an important issue, and its

Cross Hospital; Takahisa M aruyama, Osamu

results could inﬂuence the treatment of many hun-

Hasebe, Nagano M unicipal Hospital; Hiroaki

dreds of thousands of patients under antithrombotic

Yamamoto, Eigo Kojima, Nagano Chuo Hospital;

therapy.

Susumu Takahashi, Takashi Shigeno, Nagano
National Hospital;Takamori Sudo,Taro Mochizu-

Summaryki, Azumino Red Cross Hospital;Motonori Haya-

This is the ﬁrst multicenter trial in Japan toshi, Naoshi Nakamura, M arunouchi Hospital;

investigate the safety of continuing antithrombotic

Shunpei Sakurai,Kazunobu Miyata,Aizawa Hospi-

therapy during EGD with biopsy.

tal; Atsushi Sugiyama, Sugiyama Clinic; Yoshikazu Yazaki, Hideharu M iyabayashi, Matsumoto

Appendix

National Hospital; Syouji Sawaki, Oowa Osamu,

Investigators

Hata General Hospital;Mafumi Owa,Kenji Muka-

Hiroki Kasai, Tomoaki Suga, Uichi Ikeda, Eijiwa, Suwa Red Cross Hospital;Akira Kawashima,

Tanaka, Shinshu University Hospital; Taiji

Takashi Midorikawa, Okaya City Hospital; Wa-

Akamatsu, Nagano Prefectural Suzaka Hospital;

kabayashi Yasusi, Kei Kitahara, Nagano Prefec-

Jiro Yoshioka, Yoshiaki Matsuda, Nagano Red

tural Kiso Hospital;Kazuya Yamamoto,Yoshiyuki

Cross Hospital; Kazuhiro Takenaka, Iiyama Red

Nakamura, Iida Municipal Hospital.

References
1) ASGE Standards of Practice Committee, Anderson M A, Ben‑Menachem T, Gan SI, Appalaneni V, Banerjee S,
Cash BD,Fisher L,Harrison M E,Fanelli RD,Fukami N,Ikenberry SO,Jain R,Khan K,Krinsky ML,LichtensteinDR, M aple JT, Shen B, Strohmeyer L, Baron T, Dominitz JA :ASGE guideline:M anagement of antithrombotic
agents for endoscopic procedures. Gastrointest Endosc 70:1060‑1070, 20092) Gerson LB, Gage BF, Owens DK, Triadaﬁlopoulos G : Eﬀect and outcomes of the ASGE guidelines on theperiendoscopic management of patients who take anticoagulants. Am J Gastrolenterol 95:1717‑1724, 2000
3) Basson MD,Panzini L,Palmer RH :Eﬀect of nabumetone and aspirin on colonic mucosal bleeding time.Aliment
Pharmacol Ther 15:539 ‑542, 2001
4) Hui AJ, Wong RM, Ching JY, Hung LC, Chung SC, Sung JJ :Risk of colonoscopic polypectomy bleeding with
anticoagulants and antiplatelet agents:analysis of 1657 cases. Gastrointest Endosc 59 :44‑48, 2004
5) Shiﬀman M L, Farrel M T, Yee YS :Risk of bleeding after endoscopic biopsy or polypectomy in patients taking
aspirin or other NSAIDS. Gastrointest Endosc 40:458‑462, 1994
6) Sawhney MS, Salﬁti N, Nelson DB, Lederle FA, Bond JH : Risk factors for severe delayed postpolypectomy
bleeding. Endoscopy 40:115‑119, 2008
7) Hussain N, Alsulaiman R, Burtin P, Toubouti Y, Rahme E, Boivin JF, Barkun AN :The safety of endoscopic
sphincterotomy in patients receiving antiplatelet agents:a case control study.Aliment Pharmacol Ther 25:579 ‑
584, 2007
8) Zuckerman MJ, Hirota WK, Adler DG, Davila RE, Jacobson BC, Leighton JA, Qureshi WA, Rajan E,Hambrick
RD,Fanelli RD,Baron TH,Faigel DO:Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy:ASGE guideline:the management of low‑molecular‑weight heparin and nonaspirin antiplatelet
agents for endoscopic procedures. Gastrointest Endosc 61:189 ‑194, 2005
9) Ogoshi K, Kaneko E,Tada M,Mitsu T,Yoshino J,Yahagi N,Goto N :The management of anticoagulation andantiplatelet therapy for endoscopic procedures. Gastroenterol Endosc 47:2691‑2695 (in Japanese), 2005
10) Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK :Eﬀects of clopidogrel in addition to aspirin inpatients with acute coronary syndromes without ST‑segment elevation. N Engl J Med 345:494‑502, 2001
No. 3, 2012147

Kasai.Suga.Ikeda et al.
11) M a L, Elliott SN, Cirino G, Buret A, Ignarro LJ, Wallace JL :Platelets modulate gastric ulcer healing :role ofendostatin and vascular endothelial growth factor release. Proc Natl Acad Sci USA 98:6470‑6475, 2001
12) Chin M W, Yong G, Bulsara M K, Rankin J, Forbes GM :Predictive and protective factors associated with uppergastrointestinal bleeding after percutaneous coronaryintervention : a case‑control study.Am J Gastroenterol 102:
2411‑2416, 2007
13) Buresly K, Eisenberg MJ, Zhang X, Pilote L :Bleeding complications associated with combinations of aspirin,
thienopyridine derivatives, and warfarin in elderly patients following acute myocardial infarction. Arch Intern
M ed 165:784‑789, 200514) Sakata Y :Guidelines for management of anticoagulant and antiplatelet therapy in cardiovascular disease (JCS2009). Jpn J Thromb Hemost 21:365‑370 (in Japanese), 201015) Komatsu T,Tamai Y,Takami H,Yamagata K,Fukuda S,M unakata A :Study for determination of the optimal
cessation period of therapy with anti‑platelet agents prior to invasive endoscopic procedures.J Gastroenterol 40:
698‑707, 200516) Lee SY,Tang SJ,Rockey DC,Weinstein D,Lara L,Sreenarasimhaiah J,Choi KW :Managing anticoagulation andantiplatelet medications in GI endoscopy:a surveycomparing the east and the west.Gastrointest Endosc 67:1076‑
1081, 200817) Ono S, Fujishiro M , Hirano K, Niimi K, Goto O, Kodashima S, Yamamichi N, Koike K :Retrospective analysis
on the management of anticoagulants and antiplatelet agents for scheduled endoscopy.J Gastroenterol 44:1185‑
1189, 2009
18) Fujishiro M, Oda I, Yamamoto Y, Akiyama J, Ishii N, Kakushima N, Fujiwara J, Morishita S, Kawachi H,
Taniguchi H, Gotoda T : Multi‑center survey regarding the management of anticoagulation and antiplatelet
therapy for endoscopic procedures in Japan. J Gastroenterol Hepatol 24:214‑218, 2009（2011.11.10 received ; 2012. 1.23 accepted）

148

Shinshu Med J Vol.60