Endoscopy 2012; 44(02): 111-113
DOI: 10.1055/s-0031-1291620
Editorial
© Georg Thieme Verlag KG Stuttgart · New York

Should antiplatelets be stopped before gastric mucosectomy? For how long and in whom?

M. Dinis-Ribeiro
1   Department of Gastroenterology, Portuguese Oncology Institute of Porto, Portugal
2   Centre for Research in Health Technologies and Information Systems (CINTESIS), Medical Faculty, Porto, Portugal
,
P. Pimentel-Nunes
1   Department of Gastroenterology, Portuguese Oncology Institute of Porto, Portugal
› Author Affiliations
Further Information

Publication History

submitted: 27 November 2011

accepted after revision: 10 December 2011

Publication Date:
23 January 2012 (online)

Endoscopic resection techniques became standard procedures for the treatment of premalignant and early cancerous lesions in the gastrointestinal tract because of their high efficacy and relatively low morbidity when performed by adequately qualified teams at referral centers [1] [2]. Nevertheless, these techniques are associated with some important complications such as recurrence, perforation, stenosis, and, most frequently, hemorrhage. These may occur in a varying proportion of cases, best described so far with regard to the stomach. This proportion is associated both with unchangeable factors, such as lesion size and location and some patient characteristics such as age, and also with modifiable parameters, such as the technique employed, operator training, and other patient factors such as concomitant controllable diseases and/or medication [3] [4] [5] [6] [7] [8] [9].

In this issue of Endoscopy, Cho et al. publish a retrospective single-center cohort investigation into whether aspirin intake increased the risk of post-endoscopic submucosal dissection (ESD) bleeding [10].

They defined bleeding as evidence of upper gastrointestinal bleeding (e. g. melena) with a hemoglobin drop of more than 2 g/dL, without considering intraprocedural bleeding as a variable. Indeed, the definition of bleeding varies between studies and it does not seem easy to quantify or to clearly define intraprocedural bleeding since bleeding is observed during almost all ESDs. In fact, bleeding may well be considered the most frequent complication of ESD. The consequences are however variable and it has be stated that up to one third of patients may experience significant hemorrhage leading to longer procedure time or indirectly to other complications, such as perforation, or to ineffectiveness (R1 resection) [5] [9] [11]. It appears, therefore, very important that we should understand the factors associated with bleeding, particularly those that may be modified. Nevertheless, most of the time intraprocedural hemorrhage is controlled endoscopically, and so we tend to agree with the authors’ use in their study of an objective variable with obvious clinical significance.

Cho et al. showed that use of aspirin independently increases the bleeding risk after gastric ESD [10]. They observed that 21 % of those who continued aspirin intake during and after gastric ESD had bleeding, even when taking proton pump inhibitors (PPIs), compared with 3 – 4 % among patients who never used aspirin or who stopped before ESD. These results suggest that aspirin should be stopped in those at low risk for a thrombotic episode. This is a very relevant point as an increasing number of patients are taking antiplatelet agents. Moreover, the guideline of the American Society for Gastrointestinal Endoscopy (ASGE) does not include endoscopic mucosal resection (EMR) or ESD in its statements [12] and it is only recently that a guideline from the European Society of Gastrointestinal Endoscopy (ESGE) [13] considered this issue. The latter guideline recommended discontinuation of all antiplatelet agents including aspirin 5 days before the procedure, provided the patient was not at high risk for a thrombotic event, for example having a recently inserted coronary stent or recent previous stroke. In the study of Cho et al., the low thrombotic risk patients stopped aspirin 7 days before and resumed 4 weeks after the procedure, with no thrombotic complication being noticed [10]. However, concerning the ideal interval for stopping antiplatelet agents to minimize bleeding in patients undergoing gastric ESD, there was only a low level of evidence or no statement at all could be made. In most studies of the risk of bleeding after gastric ESD, antiplatelet agents were withheld prior to endoscopic resection procedures and resumed thereafter at unknown or variable intervals, with no uniform consideration of individual thrombotic risk. For instance, in the study by Tsuji et al. [7], aspirin was withheld from 3 days before and resumed immediately after the procedure, and the previous use of antiplatelet agents was associated with an increased risk of post-ESD bleeding, specifically from the margin of post-ESD ulcer; however no information was given about thrombotic risk. In three other studies, no information was given concerning the times of withdrawal and resumption of antiplatelet agents even though a consistently higher risk for bleeding was observed: Mannen et al. [5] reported bleeding in 9.1 % of patients with “daily usage of anticoagulants and/or antiplatelet drugs” (vs. 3.5 % in patients without these medications); Okada et al. [6] mention that 14.2 % of patients with “concomitant use of anticoagulant and/or antiplatelet agents” had bleeding compared with 12.6 % (not significant) of those who were not taking such medication; and in the study of Ono et al. [11], a 10.7 % rate of postoperative bleeding requiring endoscopic treatment was noticeable in the anticoagulant and antiplatelet group compared with 5.2 % (not significant) among those with no such medication. As mentioned above, in the study of Cho et al. [10] aspirin was stopped 7 days before and resumed 4 weeks after the procedure in the low thrombotic risk group and these patients did not show a higher risk of bleeding compared with patients who had never had antiplatelets, suggesting that this interval of time is enough to prevent bleeding.

Also, in the study of Cho et al., patients taking clopidogrel were asked to stop using it from 7 days before to 7 days after ESD, with continued use of aspirin, in agreement with ASGE guidelines for other procedures with an expected high risk of bleeding but for a longer period than suggested by the ESGE guideline (5 days before). However, even with this pause in clopidogrel intake, the resumption of clopidogrel combined with aspirin use was significantly associated with post-ESD bleeding (relative risk [RR] 26.71; 95 % confidence interval [CI] 7.09 – 100.53). Given the recent controversy regarding interaction between clopidogrel and PPIs, this is interesting since these results indirectly suggest that clopidogrel maintains its antiplatelet effect despite high omeprazole dosage. It also raises the questions of whether, in these patients, clopidogrel should be resumed somewhat later, for example at 2 weeks after ESD, and whether such a strategy would increase thrombotic risk.

Another interesting aspect of this study relates to the prescription and the use of PPIs, as once again no statement can be made concerning the use, dosing schedule, duration, and selection of antisecretory agents (PPIs or H2 antagonists? type of PPI? oral or intravenous?). Again, in most studies a PPI is the preferred choice for preventing bleeding but a variety of dosages, formulations, and treatment lengths are used. Cho et al. decided to start patients on oral omeprazole 20 mg twice per day at the time of the procedure and throughout the length of their hospital stay (2 – 3 days) with only 20 mg/d thereafter [10]. Tsuji et al. used lansoprazole infusion 30 mg twice per day on the day of the procedure and then oral lansoprazole for 8 weeks [7], a strategy similar to that of Okada et al [6]. Mannen et al. used intravenous H2 antagonists for 2 days followed by an oral H2 antagonist or PPI [5]. This issue can raise several questions. For example, although these differing strategies seem reasonable and equally effective, would not high risk patients, such as those who cannot stop aspirin or those using aspirin and clopidogrel, gain from a more aggressive approach such as daily PPI before the procedure, an 8 mg/h PPI perfusion on the day of the procedure and throughout the length of hospital stay (similar to the high risk peptic ulcer regimen), and then oral PPI twice per day for 14 days (the period of greatest risk of bleeding)? We do not have the answer to this question, and before we can answer it we need to know precisely what are the risk factors for post-ESD bleeding.

Thus, it seems reasonable to conclude that we consistently observe an increased risk of bleeding among patients taking aspirin during ESD and that clopidogrel, even when resumed 1 week after the procedure in patients already on aspirin, further increases the post-ESD bleeding risk. Probably, the shorter the duration of withholding these agents, the higher the risk of bleeding. On the other hand, in Cho et al.’s study, all bleedings were controlled with no major complications, and a longer period of withholding antiplatelets may increase the risk of thrombotic events as has been reported during antiplatelet cessation [14]. Therefore, if withdrawal for 5 – 7 days before may be preferable for those patients at low risk for thromboembolism, the ideal strategy for those with higher risk of thrombosis is still to be defined. However, we should also note that even for those at a higher risk and who are therefore taking aspirin and who would start clopidogrel soon after the procedure, ESD presents similar efficacy and safety rates and so we should not exclude these patients from therapy on the basis of the higher risk of bleeding [11]. We do believe, however, that more research, specifically decision analysis studies, are needed to investigate the timing of cessation and resumption of aspirin and other antiplatelet agents, and also the use of antisecretory drugs and even anticoagulants like heparin, in order to balance the risks of perioperative thromboembolism and hemorrhage, for ESD not only in the stomach but also in other organs [15].

 
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