Gastrointestinal Intervention

Gastrointest Interv 2012; 1:58 62 Contents lists available at SciVerse ScienceDirect Gastrointestinal Intervention journal homepage: www.gi-intervention.org Review Article Current guidelines for endoscopy in patients receiving antithrombotic medication Christopher J.L. Khor *, Juanda L. Hartono abstract Antiplatelet agents and anticoagulants make up the larger group of antithrombotic medications, which have seen increasing use worldwide as populations in developed countries age, and ischemic heart disease prevalence rises. Antithrombotic medications reduce the risk of thromboembolic events in susceptible individuals, but increase the risk of gastrointestinal bleeding. Cessation of antithrombotic drugs prior to endoscopic therapy has been proposed, aimed at reducing the risk of immediate and early bleeding. However, interruption of antithrombotic therapy is associated with cardiovascular risk. The peri-endoscopic management of patients at high thromboembolic risk therefore requires knowledge of both the bleeding risk associated with endoscopic procedures, and the potential risks of stopping antithrombotic therapy. Three major endoscopy organizations (British Society of Gastroenterology, American Society of Gastrointestinal Endoscopy & European Society of Gastrointestinal Endoscopy) have published guidelines aimed at providing a rational strategy for the endoscopist in managing the individual patient on antithrombotic medication. This article compares and contrasts the approach of each guideline, in an attempt at consensus. The British Society of Gastroenterology and American Society of Gastrointestinal Endoscopy guidelines address the use of both antiplatelet agents and anticoagulants during the peri-endoscopic period, while the European Society of Gastrointestinal Endoscopy guideline is focused solely on antiplatelet medication. The guidelines were formulated with reference mainly to observational studies and expert opinion, and therefore have a limited basis in evidence. A rational strategy is proposed for common scenarios encountered in gastrointestinal endoscopy, based on the published guidelines. Despite the existence of these guidelines, they serve at best as a framework for individualized management tailored to the patient s particular clinical scenario. Copyright Ó 2012, Society of Gastrointestinal Intervention. Published by Elsevier. All rights reserved. Keywords: Antiplatelet, Aspirin, Gastrointestinal endoscopy, Thienopyridine, Warfarin bleeding Introduction Antiplatelet agents and anticoagulants make up the larger group of antithrombotic medications. These drugs have seen increasing use worldwide as populations in developed countries age, and ischemic heart disease prevalence rises. The antiplatelet agents are comprised of, the non-steroidal anti-inflammatory drugs (NSAIDs), the thienopyridines (e.g., clopidogrel, prasugrel & ticlodipine) and the glycoprotein IIb/IIIa receptor inhibitors. Anticoagulants include,, heparin and the low-molecular-weight heparins. Antithrombotic medications reduce the risk of thromboembolic events in susceptible individuals, but increase the risk of gastrointestinal bleeding. 1 Cessation of antithrombotic drugs prior to endoscopic therapy has been proposed in a number of studies, aimed at reducing the risk of immediate and early bleeding. Interruption of antithrombotic therapy is however associated with cardiovascular risk; it has been estimated that about 5% of hospitalizations for acute coronary syndrome are due to discontinuation of antiplatelet therapy in patients undergoing a non-cardiovascular procedure. 2 The periendoscopic management of patients at high thromboembolic risk therefore requires knowledge of both the bleeding risk associated with endoscopic procedures, and the potential risks of stopping antithrombotic therapy. 3 The guidelines Three major endoscopy organizations have published guidelines aimed at providing a rational strategy for the endoscopist in managing the individual patient on antithrombotic medication. This paper will compare and contrast the approach of each guideline, in an attempt at consensus. Department of Gastroenterology & Hepatology, National University Hospital, 1E Kent Ridge Rd, NUHS Tower Block, Level 10, Singapore 119228, Singapore Received 10 September 2012; Revised 23 September 2012; Accepted 24 September 2012 * Corresponding author. Department of Gastroenterology & Hepatology, National University Hospital, 1E Kent Ridge Rd, NUHS Tower Block, Level 10, Singapore 119228, Singapore. E-mail address: christopher_khor@nuhs.edu.sg (C.J.L. Khor). 2213-1795/$ see front matter Copyright Ó 2012, Society of Gastrointestinal Intervention. Published by Elsevier. All rights reserved. http://dx.doi.org/10.1016/j.gii.2012.09.003

Christopher J.L. Khor and Juanda L. Hartono / Endoscopy and antithrombotic medication 59 The published guidelines, in chronological order of publication, are: (1) Guidelines for the management of anticoagulant and antiplatelet therapy in patients undergoing endoscopic procedures published by the British Society of Gastroenterology (BSG) in 2008 4 ; (2) Management of antithrombotic agents for endoscopic procedures, which is an update of two guidelines and was published by the American Society of Gastrointestinal Endoscopy: () in 2009 5 ; and (3), Endoscopy and antiplatelet agents by the European Society of Gastrointestinal Endoscopy (ESGE) published in 2011. 2 The BSG and guidelines address the use of both antiplatelet agents and anticoagulants during the peri-endoscopic period, while the ESGE guideline is focused solely on antiplatelet medication. All three guidelines stratify the risk of bleeding by procedure type (low vs. high bleeding risk) and the risk of thromboembolic events (low vs. high risk) arising from discontinuation of therapy. It is noteworthy that these guidelines were formulated with reference mainly to observational studies and expert opinion, and many of the recommendations made therefore have a limited basis in evidence. The guidelines also vary by the depth into which specific endoscopic procedures are discussed with respect to associated bleeding risk. The BSG does not discuss individual procedures. The discusses diagnostic endoscopy, colonic polypectomy, endoscopic sphincterotomy and percutaneous endoscopic gastrostomy (PEG). The ESGE guideline carries the most detailed discussion of the bleeding risks associated with all the procedures highlighted by the, but in addition reviews endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), EUS-FNA, endoscopic stent placement and dilation, device-assisted enteroscopy, endoscopic variceal ligation, and argon plasma coagulation Table 1 Bleeding Risk Stratified by Type of Endoscopic Procedure Bleeding risk Type of procedure Guideline where risk is specified Low risk for Diagnostic EGD, colonoscopy bleeding (including biopsy) Colonic polypectomy <1 cm ESGE ERCP without sphincterotomy EUS without FNA EUS-FNA of solid masses ESGE Stricture dilation ESGE Digestive stenting Argon plasma coagulation ESGE Diagnostic enteroscopy and balloon-assisted enteroscopy Capsule endoscopy bleeding ERCP with sphincterotomy, with or without balloon papillary dilation Polypectomy Stricture dilation Variceal therapy PEG placement Endoscopic hemostasis EUS with FNA Cyst-enterostomy Tumor ablation any technique EMR, ESD and ampullary resection EMR All in and BSG; >1 cm in ESGE, BSG All in, BSG; cystic lesions only, in ESGE ESGE, BSG, American Society of Gastrointestinal Endoscopy; BSG, British Society of Gastroenterology; EGD, Esophago-Gastro-Duodenoscopy; EMR, endoscopic mucosal resection; ERCP, endoscopic retrograde cholangiopancreatography; ESD, endoscopic submucosal dissection; ESGE, European Society of Gastrointestinal Endoscopy; EUS, Endoscopic Ultrasound; FNA, Fine Needle Aspiration; PEG, percutaneous endoscopic gastrostomy. Table 2 Thrombosis Risk Stratification for Discontinuation of Clopidogrel Low risk for thrombosis thrombosis Coronary DES >12 mos previously Bare metal coronary stents inserted >6 wks previously without associated risk factors Stroke without cardiac failure >6 wks previously Ischemic heart disease without coronary stents Cerebrovascular disease Peripheral vascular disease Coronary DES inserted 12 mos previously Bare metal coronary stents inserted 6 wks previously or >6 wks previously with associated risk factors Stroke 6 wks previously Acute coronary syndrome Non-stented percutaneous coronary intervention after myocardial infarction DES, drug-eluting stents. Adapted from ESGE, BSG and guidelines. (APC) hemostasis. Table 1 summarizes bleeding risk stratified by type of endoscopic procedure. Tables 2 and 3 stratify cardiovascular conditions by thromboembolic risk when antiplatelet agents and anticoagulant therapy are discontinued, respectively. Procedures at low risk of peri-endoscopic bleeding All three guidelines are in agreement that is to be continued. The BSG and recommend continuing thienopyridines. The ESGE however recommends stopping the thienopyridines for these particular scenarios although they are deemed low-risk for bleeding: removal of subcentimeter colonic polyps, stricture dilation, enteral stent placement, APC and EUS-FNA of solid lesions. Except for enteral stent placement (), these are ed high-risk procedures by the other two societies. For anticoagulants, BSG and guidelines advocate continuation at therapeutic international normalized ratio (INR). Procedures at high risk of peri-endoscopic bleeding In the main, these are procedures involving endoscopic resection and cautery, plus procedures with the potential to induce bleeding that is inaccessible to endoscopic therapy. The three guidelines each dichotomize the approach between conditions at low thromboembolic risk, and those at high thromboembolic risk, with respect to use of, thienopyridines and anticoagulants (the ESGE guideline deals only with antiplatelet agents). The general recommendation with regards to low thromboembolic risk conditions is to stop the therapy concerned before endoscopy (thienopyridine 5 7 days before, Table 3 Thromboembolic Risk Stratification for Discontinuation of Anticoagulant Therapy Low risk for thromboembolism thromboembolism Adapted from BSG and guidelines. Prosthetic metal heart valve in aortic position Bioprosthetic valve Atrial fibrillation without valvular disease Venous thromboembolism >3 mos previously Prosthetic metal heart valve in mitral position Prosthetic heart valve and atrial fibrillation Prosthetic heart valve in any position and previous thromboembolic event Atrial fibrillation with valvular heart disease, prosthetic valves, active congestive heart failure, left ventricular ejection fraction of < 35%, a history of a thromboembolic event, hypertension, diabetes mellitus, or age >75 ys Venous thromboembolism <3 mos previously Thrombophilia syndromes

60 Gastrointestinal Intervention 2012 1(1), 58 62 5 days before). For conditions associated with high thromboembolic risk the societies advise delaying endoscopy until the thienopyridine/dual antiplatelet therapy course has ended, or stopping the medication temporarily in consultation with the managing cardiologist. Consideration should also be given to performing an alternative or temporizing procedure associated with lower bleeding risk, if possible. Aspirin should be maintained in all cases, or used in place of the thienopyridine. 2 In patients taking, both BSG and recommend stopping 5 days before the procedure, and bridging with low-molecular-weight heparin. Risk of interrupting antithrombotic therapy for a procedure at higher risk of bleeding, versus the risk of peri-endoscopic bleeding when antithrombotic medication is continued Prior to performing an endoscopic procedure for a patient on antithrombotic therapy, one should first the risks of a thromboembolic event related to interruption of antithrombotic medication, and second, bleeding related to endoscopic therapy while on antithrombotic medication. One should be mindful that a thromboembolic event that may occur following withdrawal of medication can be devastating, whereas bleeding after high-risk procedures, although increased in frequency, is rarely associated with significant morbidity or mortality. 5 Conditions carrying a higher risk of thromboembolic events if antithrombotic therapy is interrupted include atrial fibrillation associated with valvular heart disease, mechanical valves in the mitral position, and mechanical valves in patients who have had a previous thromboembolic event. Study data indicate that the absolute risk of an embolic event for patients in whom anticoagulation is interrupted for 4 to 7 days is about 1%. 6,7 Patients with coronary stents are at high risk of stent thrombosis when dual antiplatelet therapy is discontinued before the minimum duration specified by the American College of Cardiology (ACC); 1 year for drug-eluting stents, and 1 month for bare metal stents. 8 One large prospective study reported a hazard ratio of 89 for stent thrombosis when antiplatelet therapy was discontinued prematurely. 9 Case fatality is extremely high, at 20% to 45%. 3,9 Patients who require dual antiplatelet therapy should always be kept on, and the decision to discontinue the thienopyridine should be taken in consultation with the attending cardiologist. The peri-endoscopic bleeding risk for patients on antithrombotic therapy may be ed by procedure; this review will focus on the procedures at higher risk of bleeding for which more evidence exists. For colonoscopic polypectomy while on or NSAIDs, the bleeding risk appears to be small. 10 Warfarin use is associated with increased bleeding risk, as is resumption of anticoagulation within 1 week of polypectomy. 10,11 Several studies of prophylactic endoclip application suggest that it keeps bleeding rates low in anticoagulated patients, but current evidence is insufficient for its routine use to be recommended. 12,13 The risk of bleeding after endoscopic sphincterotomy (ES) is 0.3% to 2%. 14 16 Withdrawal of does not appear to reduce this risk 17 ; anticoagulation with or heparin however increases the risk of postsphincterotomy bleeding. 18 Large balloon papillary dilation in combination with ES (to avoid mechanical lithotripsy for the removal of large biliary calculi) is associated with higher bleeding risk than ES alone. In PEG placement, the overall risk of bleeding is about 2.5%, 19 but the additional risk conferred by antithrombotic therapy is not known. EMR is done less frequently in the West than in the East; Western series report higher bleeding rates of 4.6% to 12%. Duodenal polypectomy is associated with higher risk of bleeding than polypectomy at other sites, and is reported as 3.1% to 11.6% in the five most recent prospective studies using EMR techniques. The technique of endoscopic ampullectomy is similar to EMR, and is associated with bleeding risk of 5.6% from five large retrospective series. 2 A recent meta-analysis showed that ESD has a two-fold risk of bleeding when compared with EMR (OR 2.20; 95% CI, 1.58 3.07). Antiplatelet agents and anticoagulants were routinely stopped ahead of all studies involving these high-risk procedures. Appendix summarizes the approach of each of the three guidelines towards the management of antithrombotic agents for endoscopic procedures at high risk for periprocedural bleeding. Urgent endoscopy in the patient with acute coronary syndrome or a recently placed coronary stent The guideline is the only one that discusses this frequently-encountered scenario in depth. An estimated 1% to 3% of patients with acute coronary syndrome (ACS) will have an associated gastrointestinal (GI) bleed, and these individuals are expected to have a four- to seven-fold increase in the risk of in-hospital mortality over those without GI bleeding. 5 The overall risk of peri-procedural complications associated with upper GI endoscopy is about 1% to 2% (1% with colonoscopy), 20,21 but may be as high as 12% for endoscopy done on the same day as the acute cardiac event. 22 The data in this setting however remains scanty. A decision analysis showed that upper endoscopy before cardiac catheterization was beneficial in patients who presented with overt GI bleed in the setting of ACS, significantly reducing overall mortality. 23 The suggests withholding antiplatelet agents until hemostasis is achieved, but qualifies that no strong recommendation can be made. Conclusion All three guidelines stratify patients by thromboembolic risk if antithrombotic therapy needs to be interrupted, but differ in the detail with which they discuss the individual endoscopic procedures. The ESGE guideline deals only with antiplatelet agents. There is general agreement among them with respect to antiplatelet therapy continuation for individuals at low risk of thromboembolism and for continuation of anticoagulant use, but broad differences are seen in the ESGE review of specific endoscopic therapies. The decision to interrupt antithrombotic therapy has to be individualized in ation of the patient s condition and procedure risks. In patients with coronary stent placement of duration shorter than the appropriate minimum stipulated by the ACC, the high risk of a thrombotic event with devastating consequences mandates that the decision to interrupt antiplatelet therapy is taken in consultation with the attending cardiologist. Conflict of Interest The author & co-author have no conflict of interest to report. References 1. Aronow HD, Steinhubl SR, Brennan DM, Berger PB, Topol EJCREDO Investigators. Bleeding risk associated with 1 year of dual antiplatelet therapy after percutaneous coronary intervention: insights from the clopidogrel for the reduction of events during observation (CREDO) trial. Am Heart J. 2009;157: 369 74.

Christopher J.L. Khor and Juanda L. Hartono / Endoscopy and antithrombotic medication 61 2. Boustiere C, Veitch A, Vanbiervliet G, Bulois P, Deprez P, Laquiere A, et al. Endoscopy and antiplatelet agents. European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy. 2011;43:445 61. 3. Montalescot G, Hulot JS, Collet JP. Stent thrombosis: who s guilty? Eur Heart J. 2009;30:2685 8. 4. Veitch AM, Baglin TP, Gershlick AH, Harnden SM, Tighe R, Cairns S, et al. Guidelines for the management of anticoagulant and antiplatelet therapy in patients undergoing endoscopic procedures. Gut. 2008;57:1322 9. 5. Standards of Practice Committee, Anderson MA, Ben-Menachem T, Gan SI, Appalaneni V, Banerjee S, et al. Management of antithrombotic agents for endoscopic procedures. Gastrointest Endosc. 2009;70:1060 70. 6. Blacker DJ, Wijdicks EF, McClelland RL. Stroke risk in anticoagulated patients with atrial fibrillation undergoing endoscopy. Neurology. 2003;61: 964 8. 7. Garcia DA, Regan S, Henault LE, Upadhyay A, Baker J, Othman M, et al. Risk of thromboembolism with short-term interruption of therapy. Arch Intern Med. 2008;168:63 9. 8. King 3rd SB, Smith Jr SC, Hirshfeld Jr JW, Jacobs AK, Morrison DA, Williams DO, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. JAm Coll Cardiol. 2008;51:172 209. 9. Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293:2126 30. 10. 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. 2004;59:44 8. 11. Sawhney MS, Salfiti N, Nelson DB, Lederle FA, Bond JH. Risk factors for severe delayed postpolypectomy bleeding. Endoscopy. 2008;40:115 9. 12. Sobrino-Faya M, Martinez S, Gomez Balado M, Lorenzo A, Iglesias-García J, Iglesias-Canle J, et al. Clips for the prevention and treatment of postpolypectomy bleeding (hemoclips in polypectomy). Rev Esp Enferm Dig. 2002;94:457 62. 13. Friedland S, Soetikno R. Colonoscopy with polypectomy in anticoagulated patients. Gastrointest Endosc. 2006;64:98 100. 14. Freeman ML. Complications of endoscopic biliary sphincterotomy: a review. Endoscopy. 1997;29:288 97. 15. Masci E, Toti G, Mariani A, Curioni S, Lomazzi A, Dinelli M, et al. Complications of diagnostic and therapeutic ERCP: a prospective multicenter study. Am J Gastroenterol. 2001;96:417 23. 16. Cotton PB, Garrow DA, Gallagher J, Romagnuolo J. Risk factors for complications after ERCP: a multivariate analysis of 11,497 procedures over 12 years. Gastrointest Endosc. 2009;70:80 8. 17. Hui CK, Lai KC, Yuen MF, Wong WM, Lam SK, Lai CL. Does withholding for one week reduce the risk of post-sphincterotomy bleeding? Aliment Pharmacol Ther. 2002;16:929 36. 18. Hussain N, Alsulaiman R, Burtin P, Toubouti Y, Rahme E, Boivin JF, et al. The safety of endoscopic sphincterotomy in patients receiving antiplatelet agents: a case-control study. Aliment Pharmacol Ther. 2007;25:579 84. 19. Schapiro GD, Edmundowicz SA. Complications of percutaneous endoscopic gastrostomy. Gastrointest Endosc Clin N Am. 1996;6:409 22. 20. Cappell MS, Iacovone Jr FM. Safety and efficacy of esophagogastroduodenoscopy after myocardial infarction. Am J Med. 1999;106:29 35. 21. Cappell MS. Safety and efficacy of colonoscopy after myocardial infarction: an analysis of 100 study patients and 100 control patients at two tertiary cardiac referral hospitals. Gastrointest Endosc. 2004;60:901 9. 22. Spier BJ, Said A, Moncher K, Pfau PR. Safety of endoscopy after myocardial infarction based on cardiovascular risk categories: a retrospective analysis of 135 patients at a tertiary referral medical center. J Clin Gastroenterol. 2007;41: 462 7. 23. Yachimski P, Hur C. Upper endoscopy in patients with acute myocardial infarction and upper gastrointestinal bleeding: results of a decision analysis. Dig Dis Sci. 2009;54:701 11.

Appendix Management of antiplatelet/anticoagulant therapy in endoscopic procedures associated with high risk of bleeding. 62 Procedure BSG 2008 2009 ESGE 2011 Continue Continue TPD Continue Continue Continue TPD Continue Continue Continue TPD Thromboembolic risk Thromboembolic risk Thromboembolic risk Low High Low High Low High Low High Low High Low High Colon polypectomy a Pneumatic or bougie dilation a Stop TPD 7 ds before scope Continue if already on, otherwise alone when TPD stopped Consult cardiologist, stopping if Stop 5 ds before endoscopy b No Postpone scope No, bridging LMWH/UFH No Use High risk: beyond minimum duration for in addition start LMWH 2 ds after b No EUS + FNA TPD therapy, continue stopping b Consider No No Endoscopic sphincterotomy Percutaneous endoscopic gastrostomy Endoscopic variceal ligation continuing/starting in dual therapy/tpd alone for patients in periendoscopic period If emergent, stopping and delaying for 7 10 ds; continuing/starting in dual therapy/tpd monotherapy patients in the periendoscopic period Stop for cystic lesions b c 1) Stop TPD 2) use blended current for the extraction of large biliary stones in patients on, mechanical lithotripsy recommended over ES+ LBD b b No Endoscopic b (no hemostasis a recommendation for DAT) EMR/ESD & ampullectomy Device-assisted enteroscopy (EMR only) (EMR only) No No No Consider stopping / instead + cardio consult Gastrointestinal Intervention 2012 1(1), 58 62 Note: From Endoscopy in the patient on antithrombotic therapy, by H Abu Daya, L Younan and AI Sharara, 2012 Curr Opin Gastroenterol 28, p.432 441. Copyright 2012, Lippincott Williams & Wilkins. Adapted with permission. DAT, dual antiplatelet therapy; EMR, endoscopic mucosal resection; ES, endoscopic sphincterotomy; ESD, endoscopic submucosal dissection; EUS, endoscopic ultrasound; FNA, fine needle aspiration; LBD, large balloon dilation; LMWH, low-molecular-weight heparin; TPD, thienopyridine; UFH, unfractionated heparin. a Colon polypectomy <1 cm, dilation of digestive stenosis, EUS with FNA of solid masses, and argon plasma coagulation (APC) are ed low-risk procedures by the ESGE. Aspirin should be continued in all these procedures, whereas thienopyridines are to be continued only in APC of angiodysplasias according to the ESGE. b Consider stopping it if possible, or else can be continued. c If large balloon papillary dilation is to be performed then should be stopped.