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Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE
Yong Chan Lee |
Professor of Medicine Director, Gastrointestinal Research Laboratory Veterans Affairs Medical Center, Univ. California San Francisco San Francisco, USA |
Jong Pil Im | Seoul National University College of Medicine, Seoul, Korea |
Robert S. Bresalier | University of Texas M. D. Anderson Cancer Center, Houston, USA |
Steven H. Itzkowitz | Mount Sinai Medical Center, NY, USA |
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Moon Kyung Joo1 , Chan Hyuk Park2 , Joon Sung Kim3 , Jae Myung Park4 , Ji Yong Ahn5 , Bong Eun Lee6 , Jeong Hoon Lee5 , Hyo-Joon Yang7 , Yu Kyung Cho4 , Chang Seok Bang8 , Beom Jin Kim9 , Hye-Kyung Jung10 , Byung-Wook Kim3 , Yong Chan Lee11 , Korean College of Helicobacter Upper Gastrointestinal Research
Correspondence to: Yong Chan Lee
Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea
Tel: +82-2-2228-1960, Fax: +82-2-393-6884, E-mail: leeyc@yuhs.ac
Can-Tong Liu and Yi-Wei Xu contributed equally to this work as first authors.
Gut Liver 2020;14(6):707-726. https://doi.org/10.5009/gnl20246
Published online November 15, 2020, Published date November 15, 2020
Copyright © Gut and Liver.
Korean guidelines for nonsteroidal anti-inflammatory drug (NSAID)-induced peptic ulcer were previously developed in 2009 with the collaboration of the Korean College of Helicobacter and Upper Gastrointestinal Research and Korean Society of Gastroenterology. However, the previous guidelines were based mainly upon a review of the relevant literature and expert opinion. Therefore, the guidelines need to be revised. We organized a guideline Development Committee for drug-related peptic ulcer under the auspices of the Korean College of Helicobacter and Upper Gastrointestinal Research in 2017 and developed nine statements, including four for NSAIDs, three for aspirin and other antiplatelet agents, and two for anticoagulants through a de novo process founded on evidence-based medicine that included a literature search and a meta-analysis, A consensus was reached through the application of the modified Delphi method. The primary target of these guidelines is adult patients undergoing long-term treatment with NSAIDs, aspirin or other antiplatelet agents and anticoagulants. The revised guidelines reflect the expert consensus and is intended to assist clinicians in the management and prevention of druginduced peptic ulcer and associated conditions.
Keywords: Peptic ulcer, Non-steroidal anti-inflammatory agents, Antiplatelet agent, Anticoagulants, Guideline
Korea has the world’s most rapidly aging population, and the prevalence of chronic diseases like osteoarthritis or cerebrovascular diseases and the corresponding financial burden on individuals and society are increasing rapidly.1,2 Furthermore, as nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin or other antiplatelet agents or anticoagulants continue to be used as a primary therapeutic agent for chronic diseases, primary care physicians frequently experience drug-induced gastrointestinal (GI) side effects. These include GI damage such as peptic ulcer (PU) or bleeding.3 Previous large-scale randomized control studies showed that the annual incidence of upper GI clinical events, which included uncomplicated symptomatic PU, by use of nonselective NSAID ranged from 2.7% to 4.5%, and that of major complications such as bleeding or perforation ranged from 1.0% to 1.5%,4-7 and other pivotal studies have shown that aspirin is the most potent risk factor for GI bleeding when combined with other antiplatelet agents, such as clopidogrel.8,9 A previous Korean multicenter cohort study showed that prevalence of
Clinical practice guidelines for drug-related PU were previously developed and published in the United States (American College of Gastroenterology),12 Canada (Canadian Association of Gastroenterology)13 and Japan (Japanese Society of Gastroenterology).14 Previously, Korean guidelines for prevention and treatment of NSAID-related PUs,15 as well as diagnosis for PU disease,16 treatment for non-bleeding PU disease,17 treatment for bleeding PU disease18 and treatment for PU disease under special conditions,19 were developed under the auspices of the Korean College of
The main target population of this clinical practice guideline is adult patients with long-term administration of NSAIDs, aspirin or other antiplatelet agents or anticoagulants, who have a history of drug-related PU and its complications or who correspond to a high-risk group. In particular, this clinical practice guideline actively reflects the contents of questions about the selection or resumption of drugs, which were frequently asked by patients who visited the outpatient department of gastroenterology, or who had undergone inpatient treatment due to PU and its complications during the long-term administration of NSAIDs, aspirin or antiplatelet agents or anticoagulants. The purpose of this clinical practice guideline therefore, is to summarize the risk factors for drug-related PU and to provide appropriate guidelines for the prevention and treatment of drug-related PUs and its complications in patients with long-term use of NSAIDs, aspirin or other antiplatelet agents and anticoagulants. It is to be hoped that this guideline, will help clinicians make decisions at the outpatient department of primary medical institutions. Furthermore, the authors aimed to provide specific guidelines for gastroenterologists, as well as orthopedic surgeons, rheumatologists, cardiologists, neurologists and other related specialists who frequently prescribe NSAIDs, aspirin or other antiplatelet agents, or anticoagulants, to effectively manage PU and its complications in the course of outpatient and inpatient treatment at secondary and tertiary medical institutions. The authors’ intent was also to provide educational materials for medical workers such as doctors and nurses in training, and to enhance the predictability of medical services and help them choose optimal treatments by providing the best standards for clinical care. Through all of these efforts, the authors intended to improve the quality of life of patients and contribute to improving national health.
This clinical practice guideline is a specific and comprehensive recommendation for the treatment of drug-related PU. This guideline was written as evidence-based recommendations rather than a list of textbook knowledge. However, in areas of clinical significance and where expert opinions are consistent, recommendations have been made by agreement even though there was a lack of specific evidence in the literature.
The clinical guideline practice committee was composed of the Steering Committee, the Development Committee and the Appraisal Committee. The Steering Committee established the strategy and direction of guidance development, appointed the relevant chairperson, and reviewed and approved the project budget. The Steering Committee also coordinated stakeholders in the development of the guideline and supervised the maintenance of editorial independence. The Development Committee was established under the Korean College of
The Development Committee reviewed previous Korean guidelines on the prevention and treatment of NSAID-related PU15 and other related guidelines16-19 which were developed under supervision of the Korean College of
The selection of key questions for the clinical practice guidelines were made primarily with the participation of all members of the Development Committee, and were finalized in consideration of external guidelines and domestic clinical practice. The key clinical questions for each subject were selected following the principle of PICO (Population, Intervention, Comparison, Outcome), and systematic literature searches were conducted on the basis of PICO (Supplementary Table 1).
2) Literature searchLiterature from January 1987 to November 2017 was systemically searched using three bibliographic databases (MEDLINE, EMBASE, and Cochrane Library) and a search engine (KoreaMed). We searched the literature with a combination of population-related index words (NSAID, aspirin, antiplatelet agent, anticoagulant, and PU) and intervention-related index words (proton pump inhibitor [PPI], microprostol, histamine-2 receptor antagonist [H2RA], and
The selected literature was qualified by Cochrane Collaboration’s Tool for Assessing the Risk of Bias if it was a randomized controlled trial (RCT),20 and by Risk of Bias Assessment tool for Non-randomized Studies (RoBANS)21 in the case of non-randomized trial. Two reviewers evaluated the literature independently, and if there was disagreement among reviewers, the final decision was made either by discussion or by arbitration of a third party. The effect of specific interventions on the results were presented as odds ratio (OR) or relative risk (RR) with 95% confidence interval (CI), respectively, using the RevMan (version 5.3.3) and the Comprehensive Meta-analysis Software 3.0 (Biostat, Englewood, NJ, USA) programs. The results of each meta-analysis were summarized using Forest plot, and the publication bias of the studies was evaluated by funnel plot. Heterogeneity was evaluated by
Based on the results of meta-analysis, 11 draft recommendations were initially made; six were about NSAID, three for aspirin, two for anticoagulants. Strength of recommendation and level of evidence were decided using GRADE (Grading of Recommendations Assessment, Development and Evaluation, http://www.gradeworkinggroup.org). Strength of recommendation was classified according to 5 grades: (1) strong for; (2) weak for; (3) strong against; (4) weak against; (5) insufficient (Table 1), and level of evidence as 4 grades: (1) high; (2) moderate; (3) low; (4) very low (Table 2). Then, downgrade or upgrade of level of evidence were considered according to the following criteria: In the case of RCT, the level of evidence was downgraded one or two grades if there was (1) risk of bias; (2) inconsistency; (3) indirectness; (4) imprecision; and (5) publication bias existed; and in case of observational study, the level of evidence was upgraded one or two grades if, (1) large effect magnitude existed; (2) if dose response existed, and (3) all plausible residual confounding and bias would reduce a demonstrated effect.22 The strength of recommendation was determined by considering not only the level of evidence but also the magnitude of the effect (the balance between benefit and harm), patients’ preferences and values, the use of resources, and the possibility of domestic application of the level of evidence. Members of the Development Committee decided on the wording and strength of the recommendations through face-to-face meetings or discussions via e-mail, taking into account the balance between the favorable and unfavorable outcomes of intervention, the quality of evidence, patients’ values and preferences, feasibility, and benefits and risk factors.
5) Agreement and acceptance of recommendationsAfter draft recommendations were extracted, the Development Committee invited academic experts representing the main user population of the related drugs, and adopted the recommendations using modified Delphi method. The experts who participated as members of the panel were as follows: current and former chairmen, secretary general and director and members of Scientific Committee of the Korean College of
Each member of the Development Committee in charge of each recommendation prepared a manuscript of the details by referring to the key questions, the process of extracting recommendations, the evidence within the literature and the minutes. Two experts (Gwang Ho Baik and Kee Don Choi) in the field of gastroenterology related to PUs who did not directly participate in the development, objectively verified the draft manuscript prepared by the Development Committee. The points identified in peer reviews were modified and reflected through the second internal discussion process. For external review by a group of experts, a draft of the clinical practice guideline, which included nine adopted and two dismissed recommendations, was presented to the 200 members of the academic society composed of specialists in gastroenterology at the 2018 annual autumn PG Course of the Korean College of
Although this guideline was developed on the academic society’s own budget without external financial support, the Development Committee operated independently of the Korean College of
This guideline was certified by the Korean Medical Association (KMA) in June 2020 and it was included in the information center for clinical practice guideline of the KMA website (https://www.guideline.or.kr/). In addition, the Development Committee intends to publish this guideline in the
For proper supervision and evaluation of the implementation of this guideline, a survey on whether the recommendations are implemented will be conducted on members of the Korean College of
Strength of recommendation: strong for, level of evidence: low
Expert opinion: completely agree (74%), mostly agree (22%), partially agree (0%), mostly disagree (4%), completely disagree (0%), not sure (0%)
The risk factors of PU and its complication in patients who receive NSAID medications have been reported in the secondary analysis of RCTs and in several observational studies.23-28 A prospective study by Laine
Therefore, we should know that the risk of PU and its complications are increased if patients are old, have a history of PU, or use multiple NSAIDs, aspirin, antiplatelet agent, anticoagulant, or steroid. In these cases, we also need an effort to prevent PU.
Strength of recommendation: strong for, level of evidence: high
Expert opinion: completely agree (88%), mostly agree (0%), partially agree (8%), mostly disagree (0%), completely disagree (0%), not sure (4%)
Benefit: preventive effect on PU and its complications
Harm: increase of antibiotic-resistant
Six RCTs compared the effect of
Strength of recommendation: strong for, level of evidence: high
Expert opinion: completely agree (78%), mostly agree (18%), partially agree (4%), mostly disagree (0%), completely disagree (0%), not sure (0%)
Benefit: preventive effect on PU and its complications
Harm: Potential adverse events of long-term PPI use (e.g., fracture, pneumonia,
Nine RCTs on the preventive effect of PPI co-administration for NSAID-induced PU were identified (Supplementary Fig. 5).32,39-46 Pooled RR (95% CI) for PU development was 0.29 (0.17 to 0.49) in the <12 weeks of NSAID use, 0.46 (0.19 to 1.14) in the 12–24 weeks of NSAID use, and 0.23 (0.17 to 0.49) in the ≥24 weeks of NSAID use. In other words, co-administration of PPIs reduced the risk of PU development by 54% to 76% compared to use of NSAID without PPIs (Supplementary Fig. 6).
In the subgroup analysis of different doses of PPIs for PU-preventive effects, standard-dose of PPIs and low-dose (maintenance dose) of PPIs were evaluated in five and eight studies, respectively (Supplementary Fig. 7). Pooled RR (95% CI) of standard-dose PPIs was 0.56 (0.31 to 1.00) and that of low-dose PPIs was 0.19 (0.12 to 0.30) (Supplementary Fig. 7). Even low-dose PPIs had a preventive effect on NSAID-induced PU. Additionally, there was no evidence that standard-dose PPIs was superior in terms of PU prevention to low-dose. In the subgroup analysis of different types of PPIs, preventive efficacy seemed to not be different across the types of PPIs, despite insufficient studies to reach a definitive conclusion (Supplementary Fig. 8).
Common adverse events of PPIs include diarrhea, nausea, vomiting, abdominal pain, and headache; however, most are mild and self-limiting.47 Nevertheless, the compliance of PPIs is low because they need to be taken before meals.48 Additionally, many observational studies have reported various adverse events associated with long-term PPI use, including fracture,49 pneumonia,50
The effect of PPIs for prevention of NSAID-induced PU has been proven through RCTs with low-risk of bias. Significant heterogeneity was identified in several studies with ≥24 weeks of NSAID use; however, the preventive effect of PPIs was confirmed in all those studies. Additionally, heterogeneity was not identified in studies with <12 weeks of NSAID use, and those with 12–24 weeks of NSAID use. Although there are potential adverse events related to long-term PPI therapy, the beneficial effect of co-administration of PPIs is greater than the potential risks in high-risk patients for NSAID-induced PU. Taken together, we recommend that high-risk patients who are taking long-term NSAID medications receive low-dose PPIs to prevent PU and its complications. However, the comparison of preventive effects between PPI dosages was derived from subgroup meta-analysis without direct comparative studies. Additionally, dose-dependent efficacy was not fully evaluated in all types of PPIs. It is difficult to conclude that the use of standard-dose PPIs is more harmful than that of low-dose PPIs. Therefore, low-dose PPIs may be considered primarily; however, standard-dose of PPIs may be used based on clinical needs.
1) Preventive effect of misoprostol in patents with long-term NSAID useThe preventive effect of misoprostol for NSAID-induced PU has been reported in 12 RCTs (Supplementary Fig. 9).58-69 Co-administration of misoprostol with NSAIDs reduced the risk of PU development by 55% to 74% compared to administration of NSAIDs alone (Supplementary Fig. 10). The effect size of misoprostol for the prevention of NSAID-induced PU was similar to that of PPIs. Depending on the duration of NSAIDs, the prevention effects on PU before 12 weeks, 12–24 weeks, and 24 weeks or later were reported in seven, five, and two studies, respectively. The pooled RR (95% CI) was 0.31 (0.20 to 0.47) in the <12 weeks, 0.26 (0.18 to 0.38) in the 12–24 weeks, and 0.45 (0.26 to 0.41) in the ≥24 weeks of duration. There was no significant difference in the preventive effects of PUs even if the duration of administration was extended.
In the subgroup analysis of misoprostol dosage, pooled RR of 400–600 μg of misoprostol was 0.32 (95% CI, 0.22 to 0.47) in eight studies, and that of 800 μg of misoprostol was also 0.32 (95% CI, 0.22 to 0.47) in five studies. There was no significant difference of preventive effect between the misoprostol dosages (Supplementary Fig. 11). Taken together, we can use misoprostol in high-risk patients who take NSAIDs who require long-term PPI therapy. However, we should consider the adverse GI events of misoprostol. In the previous meta-analysis on the efficacy and adverse events of misoprostol in NSAID users, diarrhea, abdominal pain, and nausea increased by 36%, 36%, and 26%, respectively, compared to placebo.70 Moreover, discontinuation of misoprostol caused by adverse events increased by 41% compared to placebo.70 Considering GI adverse events and low drug compliance of misoprostol, we recommend PPIs primarily for the PU prevention. However, misoprostol can be used if it is difficult to administer PPIs.
The statement, “We recommend high-risk patients who are taking long-term NSAID medications receive 400–600 μg of misoprostol to prevent PU and its complications,” formulated by the Development Committee, has not been finally adopted as a recommendation because it failed to obtain consent from more than two-thirds of the respondents in the first and second votes.
2) Preventive effect of H2RA in patents with long-term NSAID useThere were seven RCTs on the preventive effect of H2RA for NSAID-induced PU (Supplementary Fig. 12).71-77 Co-administration of H2RA with NSAIDs reduced the risk of PU development by 33% to 68% compared to administration of NSAIDs alone (Supplementary Fig. 13). Although co-administration of H2RA had a significant effect for the prevention of PU, the effect size of H2RA was relatively small compared to co-administration of PPIs or misoprostol.
Depending on the duration of NSAIDs, the prevention effects on PUs before 12 weeks, 12–24 weeks, and 24 weeks or later were reported in two, two, and five studies, respectively. The pooled RR (95% CI) was 0.32 (0.16 to 0.64) for <12 weeks, 0.67 (0.45 to 1.02) for 12–24 weeks, and 0.51 (0.41 to 0.64) for ≥24 weeks of duration (Supplementary Fig. 13). Although it is difficult to provide a definitive conclusion due to the limited number of studies and participants, the studies by Frank
In a subgroup analysis of H2RA dosage, pooled RR of standard-dose of H2RA was 0.59 (95% CI, 0.40 to 0.87) in four studies, and that of high-dose (double-dose) of H2RA was also 0.50 (95% CI, 0.40 to 0.63) in five studies. There was no significant difference of preventive effect between the H2RA dosages (Supplementary Fig. 14).
The statement, “We recommend high-risk patients who are taking long-term NSAID medications receive standard-dose of H2RA to prevent PU and its complications,” formulated by the Development Committee, has not been finally adopted as a recommendation. However, it failed to obtain consent from more than two-thirds of the respondents in the first and second votes.
Strength of recommendation: strong for, level of evidence: high
Expert opinion: completely agree (40%), mostly agree (36%), partially agree (16%), mostly disagree (0%), completely disagree (4%), not sure (4%)
Benefit: preventive effect on PU and its complications
Harm: Potentially increased risk of adverse cardiovascular events
Twenty-two RCTs comparing the risk of PU diseases between nonselective cyclooxygenase (COX) inhibitor and selective COX-2 inhibitor have been identified (Fig. 1).80-101 Use of selective COX-2 inhibitor reduced the risk of PU development by 73% to 80% compared to that of nonselective COX inhibitor (Fig. 2). The effect size of selective COX-2 inhibitor use was similar to that of co-administration of PPIs or misoprostol. In the subgroup analysis of medication duration, the pooled RR (95% CI) of selective COX-2 inhibitor use was 0.17 (0.08 to 0.36) in studies with <12 weeks, 0.27 (0.23 to 0.33) in studies with 12–24 weeks, and 0.25 (0.20 to 0.31) in studies with ≥24 weeks. In other words, the PU-preventive effect of selective COX-2 inhibitor use was confirmed regardless of the duration of medication (Fig. 2).
There was one head-to-head clinical trial comparing selective COX-2 inhibitor use and co-administration of PPIs to nonselective COX inhibitor (Supplementary Fig. 15). In this study, there was no significant difference between the groups, although selective COX-2 inhibitor tended to be superior to co-administration of PPIs with nonselective COX inhibitor (hazard ratio [HR], 0.70; 95% CI, 0.42 to 1.18) (Supplementary Fig. 16).102
The strategy of using selective COX-2 inhibitor to lower the risk of PU development is advantageous compared to co-administration of PPIs or misoprostol because it can reduce the risk without additional medication. Although unspecific abdominal pain, diarrhea, and dyspepsia were reported as common adverse events of selective COX-2 inhibitor, they were mild and the adverse event-related discontinuation rate of selective COX-2 inhibitor was significantly lower than that of nonselective COX inhibitor.83 However, attention should be paid to use in patients with high-risk of cardiovascular diseases, as selective COX-2 inhibitor can increase the risk of adverse cardiovascular events. According to the meta-analysis on adverse events associated with selective COX-2 inhibitors, this drug category increased the risk of myocardial infarction by 53% and tended to increase the risk of vascular events (RR, 1.16; 95% CI, 0.97 to 1.36).103 Therefore, if patients at high-risk of NSAID-induced PU have a low risk of cardiovascular disease, selective COX-2 inhibitor can be used for prevention of PU and its complications.
The NSAID-induced PU-preventive effect of selective COX-2 inhibitor at durations of 12–24 weeks as well as ≥24 weeks has been proven in RCTs with low risk of bias. There is the potential for adverse cardiovascular events in patients with risk of cardiovascular diseases; however, for patients with low-risk of cardiovascular diseases, we strongly recommend the use of selective COX-2 inhibitor instead of nonselective COX inhibitor because its beneficial effect outweighs the harmful.
1) Strategy for prevention of PU and its complications in patients who are taking long-term NSAIDStrategies for prevention of PU and its complications in patients who are taking long-term NSAID can be determined based on the GI risk and the cardiovascular risk (Table 3). Nonselective COX inhibitor without co-administration of other drugs can be chosen for patients with low-risk of NSAID-induced PU and low-risk of cardiovascular diseases. Patients with high-risk of cardiovascular diseases even though they have no PU risk including aging, may need administration of aspirin, antiplatelet agents, or anticoagulant. Because the risk of PU or ulcer bleeding is high in those patients, they require co-administration of PPIs when NSAIDs are administered. If patients have high GI risk but low cardiovascular risk, selective COX-2 inhibitors may be chosen as NSAIDs. Co-administration of PPIs to nonselective COX inhibitor is also expected to have a similar preventive effect as a selective COX inhibitor without PPIs.
If both the GI and cardiovascular risks are high, avoid using NSAIDs if possible. However, if NSAIDs are unavoidable, it is recommended to use nonselective NSAIDs with PPIs. If it is also difficult to administer PPIs, co-administration of misoprostol to nonselective NSAIDs may be considered while paying attention to adverse GI events including diarrhea. Otherwise, co-administration of H2RA to NSAIDs may be chosen even though its PU-preventive effect is relatively low.
Strength of recommendation: strong for, level of evidence: low
Expert opinion: completely agree (33%), mostly agree (46%), partially agree (21%), mostly disagree (0%), completely disagree (0%), not sure (0%)
Benefit: preventive effect on PU and its complications
Harm: increase of antibiotic-resistant
Two studies showed the effect of
In summary,
Strength of recommendation: strong for, level of evidence: moderate
Expert opinion: completely agree (44%), mostly agree (48%), partially agree (4%), mostly disagree (4%), completely disagree (0%), not sure (0%)
Benefit: preventive effect on PU and its complications
Harm: potential adverse events of long-term PPI use (i.e., fracture, pneumonia,
Effects of PPI on prevention of recurrent PU and its complications in patients who require long-term use of LDA (75–325 mg/day) have been reported in a total of seven RCTs (Supplementary Fig. 18).105-111 A meta-analysis of the seven RCTs included 5,181 patients (3,112 patients with concomitant aspirin and PPI use; 2,069 patients with aspirin alone or aspirin with control drug), and the duration of treatment ranged from 12 to 72 weeks. The concomitant use of PPIs and aspirin compared with the control group reduced the occurrence PU by 83% (HR, 0.17; 95% CI, 0.12 to 0.25; p<0.00001) (Supplementary Fig. 19A), with risk difference of –0.13 (95% CI, –0.1 to –0.08; p<0.00001), and number needed to treat (NNT) of 7.7 (Supplementary Fig. 19B). In the subgroup analysis of patients with GU (Supplementary Fig. 20), DU (Supplementary Fig. 21), and ulcer bleeding (Supplementary Fig. 22), concomitant PPI and aspirin use compared with control groups reduced the incidence of GU, DU, and ulcer bleeding by 78% (HR, 0.22; 95% CI, 0.13 to 0.35; p<0.00001), 91% (HR, 0.09; 95% CI, 0.03 to 0.25; p<0.00001), and 83% (HR, 0.17; 95% CI, 0.07 to 0.45; p<0.0004), respectively, and the risk difference was –0.11 (95% CI, –0.16 to –0.06; p<0.0001, NNT of 9.1), –0.04 (95% CI, –0.06 to –0.02; p<0.0001, NNT of 25), and –0.03 (95% CI, –0.08 to –0.01; p<0.10), respectively. In summary, PPI reduced the recurrence of PU and bleeding in patients requiring long-term use of LDA.
However, concomitant use of PPIs in all patients taking aspirin with a history of PU should be evaluated clinically, considering the benefits and risks of long-term administration. The studies included in the meta-analysis defined PUs as mucosal injuries or defects of 3 mm or more, suggesting that a significant number of patients with erosive or mild PUs that were not clinically significant were included in the study. In addition, Lai
Grade of recommendation: strong, Level of evidence: moderate
Experts’ opinion: completely agree (74%), mostly agree (26%), partially agree (0%), mostly disagree (0%), completely disagree (0%), not sure (0%)
Benefit: effect on reducing major cardiovascular death
Harm: risk of rebleeding
There is very limited evidence in the literature to guide proper timing of restarting antiplatelet agents in patients with PU bleeding who were taking antiplatelet agents. There was only one RCT that evaluated the risk of rebleeding and adverse cardiovascular and cerebrovascular events according to continuing or stopping aspirin in patients who were taking LDA when they developed PU bleeding (Supplementary Fig. 23).112 This study compared stopping aspirin for 8 weeks and restarting aspirin after endoscopic hemostasis in patients who were taking LDA for established cardiovascular or cerebrovascular diseases. In their findings, continuing aspirin showed a nonsignificant 2-fold increased risk of recurrent ulcer bleeding within 30 days as compared with stopping aspirin (aspirin group 10.3% vs placebo group 5.4%; absolute difference [95% CI], 4.9% points [–3.6 to 13.4]). However, continuation of aspirin significantly reduced all-cause mortality rates at 8 weeks (aspirin group 1.3% vs placebo group 12.9%; absolute difference [95% CI], 11.6% points [3.7 to 19.5]), which were mainly caused by cardiovascular, cerebrovascular, or GI events. It was necessary to downgrade the level of evidence to moderate with regard to inconsistency and imprecision because there was only one study. However, the recommendation grade was high because reduction in the risk of death and a key outcome, was significantly greater.
The Japanese Society of Gastroenterology (JSGE) and the American Society for Gastrointestinal Endoscopy (ASGE) also recommended reintroduction of aspirin immediately after hemostasis is achieved.14,113 In an exception to this, the European Society of Gastrointestinal Endoscopy (ESGE) recommended to withhold aspirin for 3 days in patients with high risk of PU bleeding (active bleeding, visible vessels, or adherent clots),114 because most recurrent bleeding with continuing aspirin developed within 3 days in the abovementioned study.112 Therefore, it is recommended that aspirin should be resumed immediately after endoscopic hemostasis in patients who need long-term maintenance of aspirin because of major cardiovascular disease.
No RCT was found to guide the timing of resumption of thienopyridine including clopidogrel or dual antiplatelet therapy following PU bleeding. Therefore, the recommendation on this was made similar to the recommendation on aspirin, an area of uncertainty which needs to be revised when further research is published in this regard (Table 4).
Grade of recommendation: strong, Level of evidence: very low
Experts’ opinion: completely agree (67%), mostly agree (29%), partially agree (4%), mostly disagree (0%), completely disagree (0%), not sure (0%)
Benefit: effect on reducing thromboembolism and mortality
Harm: risk of rebleeding
There is little evidence on when and how to restart the anticoagulant after PU bleeding in patients taking anticoagulants, and previous guidelines mentioned this issue based on expert opinion (Supplementary Fig. 24). ASGE,113 ESGE114 and Asian-Pacific guideline115 recommend that resumption of anticoagulant should be made multidisciplinary access by comprehensively considering patient’s status, importance of anticoagulant treatment, characteristics of hemorrhagic ulcer lesions, effective hemostasis, and risk of rebleeding. Cardiologists assess the thromboembolic risk in patients with atrial fibrillation and deep vein thrombosis, and endoscopists assess the rebleeding risk in GI tract. In principle, we recommended restarting anticoagulants immediately after effective hemostasis of ulcer in patients with PU bleeding who need long-term use of anticoagulants, if the risk of rebleeding is low.
Currently, ESGE114 and Asia-Pacific guideline115 recommend the use of vitamin K in patients with warfarin-related severe PU bleeding for antagonistic effects to warfarin. A previous retrospective study about the optimal timing of warfarin after endoscopic hemostasis of PU showed that rapid resumption of warfarin significantly reduced the thromboembolic risk.116 The risk of thrombosis should be assessed for each patient in order to determine the appropriate timing of resumption. Several previous retrospective studies which included patients with various thromboembolic risks117,118 showed that thrombosis and mortality were reduced without increasing the risk of rebleeding if warfarin was restarted within 7 to 30 days, however, rebleeding risk increased twice if it was started within 7 days after index bleeding. The Asian-Pacific guideline115 recommends restarting warfarin with heparin bridge therapy within 3 days of endoscopic hemostasis in high thromboembolic risk group, especially because it would take time to achieve sufficient anticoagulative effect if patients with warfarin use were given antagonists (Table 5).115,119,120 ESGE guideline114 states that resumption of warfarin should be individualized and recommends restarting warfarin between 7 to 15 days after index bleeding if possible, however, it does not mention anything with regard to heparin bridge therapy.114 Asian-Pacific guideline115 recommends intravenous administration of unfractionated heparin rather than low-molecular-weight heparin for heparin bridge therapy, because unfractionated heparin has a short half-life (1 to 2 hours) after intravenous administration, and it can be stopped quickly if rebleeding occurs.
The use of direct oral anticoagulants (DOAC) in patients with PU bleeding may be differently assessed based on the severity of bleeding, time taken till the last dose of DOAC, renal function and pharmacokinetic characteristics of a given drug. The Asian-Pacific guideline115 recommends temporally withholding the use of DOAC in patients with DOAC-related upper GI bleeding considering its short half-life. Vitamin K is not recommended due to absence of antagonistic effect for DOAC. Activated charcoals are considered in patients with unstable vital signs due to severe bleeding, if not more than 3 hours after taking DOAC because plasma concentrations of DOAC reach their maximum after 3 hours of administration. Idarucizumab is considered in patients with dabigatran-related severe bleeding. It is not common for patients taking DOAC to require antagonist, and clinicians can continue conservative management while waiting for the anticoagulant effect to disappear in most patients. ASGE,113 ESGE114 and British Society of Gastroenterology (BSG) and ESGE guideline121 does not specifically recommend the optimal timing of resumption of DOAC after endoscopic hemostasis, and Asian-Pacific guideline115 recommends restarting DOAC as soon as possible, within 3 days after discontinuation. The residual anticoagulant effect in the body decreases to a minimum within 3 days of discontinuation of DOAC due to its short half-life (12 hours) except in patients with decreased renal function. In terms of heparin bridge therapy till resumption of DOAC, Asian-Pacific guideline117 does not recommend the bridge therapy considering the rapid time of action of DOAC (1 to 4 hours), while ESGE guideline114 recommends bridge therapy with unfractionated heparin or low-molecular-weight heparin rather than immediate use of therapeutic dose of DOAC, then restarting the therapeutic dose of DOAC after disappearance of rebleeding risk.
In summary, evidence about optimal timing and method of resumption of anticoagulants in patients with PU bleeding during long-term use of anticoagulants are severely lacking, however, we recommend restarting anticoagulants as soon as possible immediately following endoscopic hemostasis of PU bleeding for patients who need long-term anticoagulant therapy. The optimal timing and details of restarting are determined by comprehensively considering patients’ rebleeding risk, type and pharmacokinetic characteristics of given anticoagulants, and thromboembolic risk (Table 6).115,122,123
Strength of recommendation: weak for, level of evidence: low
Expert opinion: completely agree (38%), mostly agree (46%), partially agree (16%), mostly disagree (0%), completely disagree (0%), not sure (0%)
Benefit: preventive effect on upper GI hemorrhage
Hazard: low drug adherence, potential adverse events of long-term PPI use (e.g., fracture, pneumonia,
Six nested case-control or cohort studies (three case-control124-126 and three cohort studies127-129) which evaluated the protective effect of acid suppressants against anticoagulant-related GI hemorrhage were identified through the systematic review (Supplementary Fig. 25). PPI had a protective effect against upper GI hemorrhage in patients on dicumarinics (RR, 0.56; 95% CI, 0.38 to 0.83;
However, the H2RA did not show the same effect (RR, 0.97; 95% CI, 0.52 to 1.81;
Although findings in the meta-analyses suggested the protective effect of PPIs for the development of dicumarinic-related upper GI hemorrhage, this effect was attenuated by or limited due to the high baseline risk of GI injury found consistently in the enrolled studies.124,126,128,129 Moreover, less potent inhibition of gastric acid by H2RA showed a nonsignificant protective effect, suggesting that baseline ulcerogenic properties (preexistent erosion or ulcers on the upper GI tract,
Only two studies were included in the analysis of acid suppressants on dabigatran-related GI bleeding.127,128 It was impossible to differentiate the location of GI hemorrhage (upper vs lower) and type of acid suppressants (PPI vs H2RA). Acid suppressants did not have a protective effect against GI hemorrhage in patients on dabigatran (HR, 0.78; 95% CI, 0.44 to 1.37;
Interactions from co-administration of PPIs and oral factor Xa inhibitors (xabans) does not appear to be of significant concern based on previous studies.131,134,135 However, the interaction of PPIs and the direct thrombin inhibitor dabigatran was reported (low on-treatment level of dabigatran) from recently published studies.136-138 Potential adverse events related to the long-term use of PPIs is another concern. Therefore, balancing the risk-benefit approach is still necessary before the co-prescription of anticoagulants and acid suppressants.
Based on the evidence above, we suggest high-risk patients who are taking anticoagulants to be administered PPIs to prevent upper GI hemorrhage. In cases with PPI and warfarin co-administration, close monitoring of prothrombin time with dose adjustment is needed. In terms of DOAC, little is known about risk and benefit of PPI co-administration. Considering the number of enrolled studies in this systematic review is small and all the studies were conducted in a retrospective manner, strength of recommendation is weak and the level of evidence is low. In the absence of randomized trials demonstrating a lack of bias, solid conclusions cannot be drawn.
The incidence of drug-related PU and its complications are expected to continue to increase due to the aging of the domestic population and the increase in prevalence of major comorbidities, which will not only seriously threaten the health of elderly patients, but also increase the mortality rate, and likely result in huge costs in medical expenses nationwide.139 Therefore, publishing and disseminating the appropriate clinical practice guidelines for patients with drug-related PU is an extremely valuable task, not only in terms of medical development but also in the pursuit of social public interest through health promotion. In the future, it will be necessary to perform additional major literature searches to better define the characteristics and optimal management of drug-related PU, and revise clinical practice guidelines to keep pace with the rapidly changing medical environment.
These guidelines are being co-published on the
We would like to express deep thanks to Manager Eun Ju Lee (Medical Library of Korea University), Doctor Myung Han Hyun (Korea University Guro Hospital), Manager Na-Jin Kim and Seung-Jae Lee (Medical Library of Catholic University Songeui Campus), who initially searched the literature by each key clinical question for systematic review; Professor Gwang Ho Baik (Department of Internal Medicine, Hallym University College of Medicine) and Kee Don Choi (Department of Internal Medicine, University of Ulsan College of Medicine), who reviewed the draft manuscript and advised through peer review, and Doctor Hyun Jung Kim (Korea University College of Medicine) and Ein Soon Shin (Research Institute for Healthcare Policy, Korean Medical Association), who gave lectures and advice at the clinic guideline workshop and reviewed and corrected the methodology of the draft recommendations.
No potential conflict of interest relevant to this article was reported.
Data analysis and writing - original draft: M.K.J, C.H.P., J.S.K., J.M.P., J.Y.A., B.E.L., J.H.L., H.J.Y., Y.K.C., C.S.B., B.J.K., H.K.J., B.W.K. Study design: H.K.J., B.W.K., Y.C.L. Writing - review and editing: M.K.J., C.H.P., H.K.J., B.W.K., Y.C.L. Advice on the study design: H.K.J., B.W.K., Y.C.L. Statistical support and data acquisition: H.K.J., B.W.K. All authors have read and approved the manuscript.
Strength of Recommendation
Strength of recommendation | Interpretation |
---|---|
Strong for | The benefit of the intervention is greater than the harm and the level of evidence is high, which is strongly recommended in most clinical situations. |
Weak for | The benefit of the intervention may vary depending on the clinical situation of the intervention or the patient/social value, and is recommended to be used selectively or conditionally. |
Strong against | The harm of the intervention is greater than the benefit and the level of evidence is high or the size of effectiveness is unclear and the level of evidence is low, which is recommended not to be used. |
Weak against | The harm of the intervention may vary depending on the clinical situation of the intervention or the patient/social value, and is recommended not to be used selectively or conditionally. |
Insufficient | Evidence to judge the size of effectiveness of the intervention or the level of evidence is insufficient, and it is not possible to decide whether or not to recommend until further research evidence is accumulated. |
Level of Evidence
Quality level | Interpretation |
---|---|
High | We are very confident that the true effect lies close to that of the estimate of the effect. |
Moderate | We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. |
Low | Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. |
Very low | We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect. |
Recommendations Regarding NSAID Use According to the Risk of NSAID-Induced Ulcer and Cardiovascular Disease
Risk of NSAID-induced ulcer or complication | |||
Low | High | ||
- Old age | |||
- Peptic ulcer history | |||
- Use of high dose of NSAID | |||
- Concomitant use of aspirin, antiplatelet agent, anticoagulant, or steroid | |||
Risk of cardiovascular disease | Low | Use nonselective COX inhibitors | (1) Use selective COX-2 inhibitors, or |
(2) Add proton pump inhibitors to nonselective COX inhibitors | |||
High* | Add proton pump inhibitors to nonselective COX inhibitors | (1) Avoid NSAIDs, if possible | |
(2) Add proton pump inhibitors to nonselective COX inhibitors, if NSAIDs cannot be stopped |
NSAID, nonsteroidal anti-inflammatory drug; COX, cyclooxygenase.
*Aspirin, antiplatelet agent, or anticoagulant users for the prevention of serious cardiovascular events.
Recommendation Regarding Restarting Antiplatelet Agents According to the Medicine Classification
Patents | Antiplatelet agents | Recommendation | Level of recommendation | Level of evidence |
---|---|---|---|---|
Antiplatelet use for secondary prophylaxis of known cardiovascular disease | Aspirin | Restart after endoscopic hemostasis | Strong | High |
Other agents (e.g. P2Y12 receptor inhibitor) | Restart after endoscopic hemostasis | Strong | Low | |
Dual antiplatelet therapy (DAPT) | Restart aspirin after endoscopic hemostasis. Early cardiology consultation for resuming the second antiplatelet agent. |
Strong | Low |
Indications for Heparin Bridging for the Temporary Discontinuation of Warfarin113
Non-valvular atrial fibrillation with a CHA2DS2-VASc score >5* |
Metallic mitral valve |
Prosthetic valve with atrial fibrillation |
<3 Months after venous thromboembolism |
Severe thrombophilia (protein C or protein S deficiency, antiphospholipid syndrome) |
*CHA2DS2-VASc, congestive heart failure (1 point), hypertension (1 point), age ≥75 years (2 points), diabetes mellitus (1 point), stroke, transient ischemic attack, or thromboembolism (2 points), vascular disease (1 point), age 65–74 years (1 point), female sex (1 point).117,118
Thrombotic Risk According to Cardiac Events113
Thrombotic risk category | Cardiac events |
---|---|
Very high | ACS or PCI <6 weeks |
High | ACS or PCI 6 weeks to 6 months ago |
Moderate to low | ACS or PCI >6 months ago; stable coronary artery disease |
New-generation drug-eluting stents and bare-metal stents carry similar thrombotic risks. The risk is highest within the first 6 weeks after PCI. The risk remains high from 6 weeks to 6 months, then remains constant thereafter.120,121
ACS, acute coronary syndrome; PCI, percutaneous coronary intervention.
Gut and Liver 2020; 14(6): 707-726
Published online November 15, 2020 https://doi.org/10.5009/gnl20246
Copyright © Gut and Liver.
Moon Kyung Joo1 , Chan Hyuk Park2 , Joon Sung Kim3 , Jae Myung Park4 , Ji Yong Ahn5 , Bong Eun Lee6 , Jeong Hoon Lee5 , Hyo-Joon Yang7 , Yu Kyung Cho4 , Chang Seok Bang8 , Beom Jin Kim9 , Hye-Kyung Jung10 , Byung-Wook Kim3 , Yong Chan Lee11 , Korean College of Helicobacter Upper Gastrointestinal Research
1Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, 2Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, 3Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 4Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 5Department of Gastroenterology, Asan Medical Center, Asan Digestive Disease Research Institute, University of Ulsan College of Medicine, Seoul, 6Departments of Internal Medicine, Pusan National University School of Medicine, Busan, 7Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 8Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, 9Department of Internal Medicine, Chung-Ang University College of Medicine, 10Department of Internal Medicine, Ewha Womans University College of Medicine, and 11Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
Correspondence to:Yong Chan Lee
Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea
Tel: +82-2-2228-1960, Fax: +82-2-393-6884, E-mail: leeyc@yuhs.ac
Can-Tong Liu and Yi-Wei Xu contributed equally to this work as first authors.
Korean guidelines for nonsteroidal anti-inflammatory drug (NSAID)-induced peptic ulcer were previously developed in 2009 with the collaboration of the Korean College of Helicobacter and Upper Gastrointestinal Research and Korean Society of Gastroenterology. However, the previous guidelines were based mainly upon a review of the relevant literature and expert opinion. Therefore, the guidelines need to be revised. We organized a guideline Development Committee for drug-related peptic ulcer under the auspices of the Korean College of Helicobacter and Upper Gastrointestinal Research in 2017 and developed nine statements, including four for NSAIDs, three for aspirin and other antiplatelet agents, and two for anticoagulants through a de novo process founded on evidence-based medicine that included a literature search and a meta-analysis, A consensus was reached through the application of the modified Delphi method. The primary target of these guidelines is adult patients undergoing long-term treatment with NSAIDs, aspirin or other antiplatelet agents and anticoagulants. The revised guidelines reflect the expert consensus and is intended to assist clinicians in the management and prevention of druginduced peptic ulcer and associated conditions.
Keywords: Peptic ulcer, Non-steroidal anti-inflammatory agents, Antiplatelet agent, Anticoagulants, Guideline
Korea has the world’s most rapidly aging population, and the prevalence of chronic diseases like osteoarthritis or cerebrovascular diseases and the corresponding financial burden on individuals and society are increasing rapidly.1,2 Furthermore, as nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin or other antiplatelet agents or anticoagulants continue to be used as a primary therapeutic agent for chronic diseases, primary care physicians frequently experience drug-induced gastrointestinal (GI) side effects. These include GI damage such as peptic ulcer (PU) or bleeding.3 Previous large-scale randomized control studies showed that the annual incidence of upper GI clinical events, which included uncomplicated symptomatic PU, by use of nonselective NSAID ranged from 2.7% to 4.5%, and that of major complications such as bleeding or perforation ranged from 1.0% to 1.5%,4-7 and other pivotal studies have shown that aspirin is the most potent risk factor for GI bleeding when combined with other antiplatelet agents, such as clopidogrel.8,9 A previous Korean multicenter cohort study showed that prevalence of
Clinical practice guidelines for drug-related PU were previously developed and published in the United States (American College of Gastroenterology),12 Canada (Canadian Association of Gastroenterology)13 and Japan (Japanese Society of Gastroenterology).14 Previously, Korean guidelines for prevention and treatment of NSAID-related PUs,15 as well as diagnosis for PU disease,16 treatment for non-bleeding PU disease,17 treatment for bleeding PU disease18 and treatment for PU disease under special conditions,19 were developed under the auspices of the Korean College of
The main target population of this clinical practice guideline is adult patients with long-term administration of NSAIDs, aspirin or other antiplatelet agents or anticoagulants, who have a history of drug-related PU and its complications or who correspond to a high-risk group. In particular, this clinical practice guideline actively reflects the contents of questions about the selection or resumption of drugs, which were frequently asked by patients who visited the outpatient department of gastroenterology, or who had undergone inpatient treatment due to PU and its complications during the long-term administration of NSAIDs, aspirin or antiplatelet agents or anticoagulants. The purpose of this clinical practice guideline therefore, is to summarize the risk factors for drug-related PU and to provide appropriate guidelines for the prevention and treatment of drug-related PUs and its complications in patients with long-term use of NSAIDs, aspirin or other antiplatelet agents and anticoagulants. It is to be hoped that this guideline, will help clinicians make decisions at the outpatient department of primary medical institutions. Furthermore, the authors aimed to provide specific guidelines for gastroenterologists, as well as orthopedic surgeons, rheumatologists, cardiologists, neurologists and other related specialists who frequently prescribe NSAIDs, aspirin or other antiplatelet agents, or anticoagulants, to effectively manage PU and its complications in the course of outpatient and inpatient treatment at secondary and tertiary medical institutions. The authors’ intent was also to provide educational materials for medical workers such as doctors and nurses in training, and to enhance the predictability of medical services and help them choose optimal treatments by providing the best standards for clinical care. Through all of these efforts, the authors intended to improve the quality of life of patients and contribute to improving national health.
This clinical practice guideline is a specific and comprehensive recommendation for the treatment of drug-related PU. This guideline was written as evidence-based recommendations rather than a list of textbook knowledge. However, in areas of clinical significance and where expert opinions are consistent, recommendations have been made by agreement even though there was a lack of specific evidence in the literature.
The clinical guideline practice committee was composed of the Steering Committee, the Development Committee and the Appraisal Committee. The Steering Committee established the strategy and direction of guidance development, appointed the relevant chairperson, and reviewed and approved the project budget. The Steering Committee also coordinated stakeholders in the development of the guideline and supervised the maintenance of editorial independence. The Development Committee was established under the Korean College of
The Development Committee reviewed previous Korean guidelines on the prevention and treatment of NSAID-related PU15 and other related guidelines16-19 which were developed under supervision of the Korean College of
The selection of key questions for the clinical practice guidelines were made primarily with the participation of all members of the Development Committee, and were finalized in consideration of external guidelines and domestic clinical practice. The key clinical questions for each subject were selected following the principle of PICO (Population, Intervention, Comparison, Outcome), and systematic literature searches were conducted on the basis of PICO (Supplementary Table 1).
2) Literature searchLiterature from January 1987 to November 2017 was systemically searched using three bibliographic databases (MEDLINE, EMBASE, and Cochrane Library) and a search engine (KoreaMed). We searched the literature with a combination of population-related index words (NSAID, aspirin, antiplatelet agent, anticoagulant, and PU) and intervention-related index words (proton pump inhibitor [PPI], microprostol, histamine-2 receptor antagonist [H2RA], and
The selected literature was qualified by Cochrane Collaboration’s Tool for Assessing the Risk of Bias if it was a randomized controlled trial (RCT),20 and by Risk of Bias Assessment tool for Non-randomized Studies (RoBANS)21 in the case of non-randomized trial. Two reviewers evaluated the literature independently, and if there was disagreement among reviewers, the final decision was made either by discussion or by arbitration of a third party. The effect of specific interventions on the results were presented as odds ratio (OR) or relative risk (RR) with 95% confidence interval (CI), respectively, using the RevMan (version 5.3.3) and the Comprehensive Meta-analysis Software 3.0 (Biostat, Englewood, NJ, USA) programs. The results of each meta-analysis were summarized using Forest plot, and the publication bias of the studies was evaluated by funnel plot. Heterogeneity was evaluated by
Based on the results of meta-analysis, 11 draft recommendations were initially made; six were about NSAID, three for aspirin, two for anticoagulants. Strength of recommendation and level of evidence were decided using GRADE (Grading of Recommendations Assessment, Development and Evaluation, http://www.gradeworkinggroup.org). Strength of recommendation was classified according to 5 grades: (1) strong for; (2) weak for; (3) strong against; (4) weak against; (5) insufficient (Table 1), and level of evidence as 4 grades: (1) high; (2) moderate; (3) low; (4) very low (Table 2). Then, downgrade or upgrade of level of evidence were considered according to the following criteria: In the case of RCT, the level of evidence was downgraded one or two grades if there was (1) risk of bias; (2) inconsistency; (3) indirectness; (4) imprecision; and (5) publication bias existed; and in case of observational study, the level of evidence was upgraded one or two grades if, (1) large effect magnitude existed; (2) if dose response existed, and (3) all plausible residual confounding and bias would reduce a demonstrated effect.22 The strength of recommendation was determined by considering not only the level of evidence but also the magnitude of the effect (the balance between benefit and harm), patients’ preferences and values, the use of resources, and the possibility of domestic application of the level of evidence. Members of the Development Committee decided on the wording and strength of the recommendations through face-to-face meetings or discussions via e-mail, taking into account the balance between the favorable and unfavorable outcomes of intervention, the quality of evidence, patients’ values and preferences, feasibility, and benefits and risk factors.
5) Agreement and acceptance of recommendationsAfter draft recommendations were extracted, the Development Committee invited academic experts representing the main user population of the related drugs, and adopted the recommendations using modified Delphi method. The experts who participated as members of the panel were as follows: current and former chairmen, secretary general and director and members of Scientific Committee of the Korean College of
Each member of the Development Committee in charge of each recommendation prepared a manuscript of the details by referring to the key questions, the process of extracting recommendations, the evidence within the literature and the minutes. Two experts (Gwang Ho Baik and Kee Don Choi) in the field of gastroenterology related to PUs who did not directly participate in the development, objectively verified the draft manuscript prepared by the Development Committee. The points identified in peer reviews were modified and reflected through the second internal discussion process. For external review by a group of experts, a draft of the clinical practice guideline, which included nine adopted and two dismissed recommendations, was presented to the 200 members of the academic society composed of specialists in gastroenterology at the 2018 annual autumn PG Course of the Korean College of
Although this guideline was developed on the academic society’s own budget without external financial support, the Development Committee operated independently of the Korean College of
This guideline was certified by the Korean Medical Association (KMA) in June 2020 and it was included in the information center for clinical practice guideline of the KMA website (https://www.guideline.or.kr/). In addition, the Development Committee intends to publish this guideline in the
For proper supervision and evaluation of the implementation of this guideline, a survey on whether the recommendations are implemented will be conducted on members of the Korean College of
Strength of recommendation: strong for, level of evidence: low
Expert opinion: completely agree (74%), mostly agree (22%), partially agree (0%), mostly disagree (4%), completely disagree (0%), not sure (0%)
The risk factors of PU and its complication in patients who receive NSAID medications have been reported in the secondary analysis of RCTs and in several observational studies.23-28 A prospective study by Laine
Therefore, we should know that the risk of PU and its complications are increased if patients are old, have a history of PU, or use multiple NSAIDs, aspirin, antiplatelet agent, anticoagulant, or steroid. In these cases, we also need an effort to prevent PU.
Strength of recommendation: strong for, level of evidence: high
Expert opinion: completely agree (88%), mostly agree (0%), partially agree (8%), mostly disagree (0%), completely disagree (0%), not sure (4%)
Benefit: preventive effect on PU and its complications
Harm: increase of antibiotic-resistant
Six RCTs compared the effect of
Strength of recommendation: strong for, level of evidence: high
Expert opinion: completely agree (78%), mostly agree (18%), partially agree (4%), mostly disagree (0%), completely disagree (0%), not sure (0%)
Benefit: preventive effect on PU and its complications
Harm: Potential adverse events of long-term PPI use (e.g., fracture, pneumonia,
Nine RCTs on the preventive effect of PPI co-administration for NSAID-induced PU were identified (Supplementary Fig. 5).32,39-46 Pooled RR (95% CI) for PU development was 0.29 (0.17 to 0.49) in the <12 weeks of NSAID use, 0.46 (0.19 to 1.14) in the 12–24 weeks of NSAID use, and 0.23 (0.17 to 0.49) in the ≥24 weeks of NSAID use. In other words, co-administration of PPIs reduced the risk of PU development by 54% to 76% compared to use of NSAID without PPIs (Supplementary Fig. 6).
In the subgroup analysis of different doses of PPIs for PU-preventive effects, standard-dose of PPIs and low-dose (maintenance dose) of PPIs were evaluated in five and eight studies, respectively (Supplementary Fig. 7). Pooled RR (95% CI) of standard-dose PPIs was 0.56 (0.31 to 1.00) and that of low-dose PPIs was 0.19 (0.12 to 0.30) (Supplementary Fig. 7). Even low-dose PPIs had a preventive effect on NSAID-induced PU. Additionally, there was no evidence that standard-dose PPIs was superior in terms of PU prevention to low-dose. In the subgroup analysis of different types of PPIs, preventive efficacy seemed to not be different across the types of PPIs, despite insufficient studies to reach a definitive conclusion (Supplementary Fig. 8).
Common adverse events of PPIs include diarrhea, nausea, vomiting, abdominal pain, and headache; however, most are mild and self-limiting.47 Nevertheless, the compliance of PPIs is low because they need to be taken before meals.48 Additionally, many observational studies have reported various adverse events associated with long-term PPI use, including fracture,49 pneumonia,50
The effect of PPIs for prevention of NSAID-induced PU has been proven through RCTs with low-risk of bias. Significant heterogeneity was identified in several studies with ≥24 weeks of NSAID use; however, the preventive effect of PPIs was confirmed in all those studies. Additionally, heterogeneity was not identified in studies with <12 weeks of NSAID use, and those with 12–24 weeks of NSAID use. Although there are potential adverse events related to long-term PPI therapy, the beneficial effect of co-administration of PPIs is greater than the potential risks in high-risk patients for NSAID-induced PU. Taken together, we recommend that high-risk patients who are taking long-term NSAID medications receive low-dose PPIs to prevent PU and its complications. However, the comparison of preventive effects between PPI dosages was derived from subgroup meta-analysis without direct comparative studies. Additionally, dose-dependent efficacy was not fully evaluated in all types of PPIs. It is difficult to conclude that the use of standard-dose PPIs is more harmful than that of low-dose PPIs. Therefore, low-dose PPIs may be considered primarily; however, standard-dose of PPIs may be used based on clinical needs.
1) Preventive effect of misoprostol in patents with long-term NSAID useThe preventive effect of misoprostol for NSAID-induced PU has been reported in 12 RCTs (Supplementary Fig. 9).58-69 Co-administration of misoprostol with NSAIDs reduced the risk of PU development by 55% to 74% compared to administration of NSAIDs alone (Supplementary Fig. 10). The effect size of misoprostol for the prevention of NSAID-induced PU was similar to that of PPIs. Depending on the duration of NSAIDs, the prevention effects on PU before 12 weeks, 12–24 weeks, and 24 weeks or later were reported in seven, five, and two studies, respectively. The pooled RR (95% CI) was 0.31 (0.20 to 0.47) in the <12 weeks, 0.26 (0.18 to 0.38) in the 12–24 weeks, and 0.45 (0.26 to 0.41) in the ≥24 weeks of duration. There was no significant difference in the preventive effects of PUs even if the duration of administration was extended.
In the subgroup analysis of misoprostol dosage, pooled RR of 400–600 μg of misoprostol was 0.32 (95% CI, 0.22 to 0.47) in eight studies, and that of 800 μg of misoprostol was also 0.32 (95% CI, 0.22 to 0.47) in five studies. There was no significant difference of preventive effect between the misoprostol dosages (Supplementary Fig. 11). Taken together, we can use misoprostol in high-risk patients who take NSAIDs who require long-term PPI therapy. However, we should consider the adverse GI events of misoprostol. In the previous meta-analysis on the efficacy and adverse events of misoprostol in NSAID users, diarrhea, abdominal pain, and nausea increased by 36%, 36%, and 26%, respectively, compared to placebo.70 Moreover, discontinuation of misoprostol caused by adverse events increased by 41% compared to placebo.70 Considering GI adverse events and low drug compliance of misoprostol, we recommend PPIs primarily for the PU prevention. However, misoprostol can be used if it is difficult to administer PPIs.
The statement, “We recommend high-risk patients who are taking long-term NSAID medications receive 400–600 μg of misoprostol to prevent PU and its complications,” formulated by the Development Committee, has not been finally adopted as a recommendation because it failed to obtain consent from more than two-thirds of the respondents in the first and second votes.
2) Preventive effect of H2RA in patents with long-term NSAID useThere were seven RCTs on the preventive effect of H2RA for NSAID-induced PU (Supplementary Fig. 12).71-77 Co-administration of H2RA with NSAIDs reduced the risk of PU development by 33% to 68% compared to administration of NSAIDs alone (Supplementary Fig. 13). Although co-administration of H2RA had a significant effect for the prevention of PU, the effect size of H2RA was relatively small compared to co-administration of PPIs or misoprostol.
Depending on the duration of NSAIDs, the prevention effects on PUs before 12 weeks, 12–24 weeks, and 24 weeks or later were reported in two, two, and five studies, respectively. The pooled RR (95% CI) was 0.32 (0.16 to 0.64) for <12 weeks, 0.67 (0.45 to 1.02) for 12–24 weeks, and 0.51 (0.41 to 0.64) for ≥24 weeks of duration (Supplementary Fig. 13). Although it is difficult to provide a definitive conclusion due to the limited number of studies and participants, the studies by Frank
In a subgroup analysis of H2RA dosage, pooled RR of standard-dose of H2RA was 0.59 (95% CI, 0.40 to 0.87) in four studies, and that of high-dose (double-dose) of H2RA was also 0.50 (95% CI, 0.40 to 0.63) in five studies. There was no significant difference of preventive effect between the H2RA dosages (Supplementary Fig. 14).
The statement, “We recommend high-risk patients who are taking long-term NSAID medications receive standard-dose of H2RA to prevent PU and its complications,” formulated by the Development Committee, has not been finally adopted as a recommendation. However, it failed to obtain consent from more than two-thirds of the respondents in the first and second votes.
Strength of recommendation: strong for, level of evidence: high
Expert opinion: completely agree (40%), mostly agree (36%), partially agree (16%), mostly disagree (0%), completely disagree (4%), not sure (4%)
Benefit: preventive effect on PU and its complications
Harm: Potentially increased risk of adverse cardiovascular events
Twenty-two RCTs comparing the risk of PU diseases between nonselective cyclooxygenase (COX) inhibitor and selective COX-2 inhibitor have been identified (Fig. 1).80-101 Use of selective COX-2 inhibitor reduced the risk of PU development by 73% to 80% compared to that of nonselective COX inhibitor (Fig. 2). The effect size of selective COX-2 inhibitor use was similar to that of co-administration of PPIs or misoprostol. In the subgroup analysis of medication duration, the pooled RR (95% CI) of selective COX-2 inhibitor use was 0.17 (0.08 to 0.36) in studies with <12 weeks, 0.27 (0.23 to 0.33) in studies with 12–24 weeks, and 0.25 (0.20 to 0.31) in studies with ≥24 weeks. In other words, the PU-preventive effect of selective COX-2 inhibitor use was confirmed regardless of the duration of medication (Fig. 2).
There was one head-to-head clinical trial comparing selective COX-2 inhibitor use and co-administration of PPIs to nonselective COX inhibitor (Supplementary Fig. 15). In this study, there was no significant difference between the groups, although selective COX-2 inhibitor tended to be superior to co-administration of PPIs with nonselective COX inhibitor (hazard ratio [HR], 0.70; 95% CI, 0.42 to 1.18) (Supplementary Fig. 16).102
The strategy of using selective COX-2 inhibitor to lower the risk of PU development is advantageous compared to co-administration of PPIs or misoprostol because it can reduce the risk without additional medication. Although unspecific abdominal pain, diarrhea, and dyspepsia were reported as common adverse events of selective COX-2 inhibitor, they were mild and the adverse event-related discontinuation rate of selective COX-2 inhibitor was significantly lower than that of nonselective COX inhibitor.83 However, attention should be paid to use in patients with high-risk of cardiovascular diseases, as selective COX-2 inhibitor can increase the risk of adverse cardiovascular events. According to the meta-analysis on adverse events associated with selective COX-2 inhibitors, this drug category increased the risk of myocardial infarction by 53% and tended to increase the risk of vascular events (RR, 1.16; 95% CI, 0.97 to 1.36).103 Therefore, if patients at high-risk of NSAID-induced PU have a low risk of cardiovascular disease, selective COX-2 inhibitor can be used for prevention of PU and its complications.
The NSAID-induced PU-preventive effect of selective COX-2 inhibitor at durations of 12–24 weeks as well as ≥24 weeks has been proven in RCTs with low risk of bias. There is the potential for adverse cardiovascular events in patients with risk of cardiovascular diseases; however, for patients with low-risk of cardiovascular diseases, we strongly recommend the use of selective COX-2 inhibitor instead of nonselective COX inhibitor because its beneficial effect outweighs the harmful.
1) Strategy for prevention of PU and its complications in patients who are taking long-term NSAIDStrategies for prevention of PU and its complications in patients who are taking long-term NSAID can be determined based on the GI risk and the cardiovascular risk (Table 3). Nonselective COX inhibitor without co-administration of other drugs can be chosen for patients with low-risk of NSAID-induced PU and low-risk of cardiovascular diseases. Patients with high-risk of cardiovascular diseases even though they have no PU risk including aging, may need administration of aspirin, antiplatelet agents, or anticoagulant. Because the risk of PU or ulcer bleeding is high in those patients, they require co-administration of PPIs when NSAIDs are administered. If patients have high GI risk but low cardiovascular risk, selective COX-2 inhibitors may be chosen as NSAIDs. Co-administration of PPIs to nonselective COX inhibitor is also expected to have a similar preventive effect as a selective COX inhibitor without PPIs.
If both the GI and cardiovascular risks are high, avoid using NSAIDs if possible. However, if NSAIDs are unavoidable, it is recommended to use nonselective NSAIDs with PPIs. If it is also difficult to administer PPIs, co-administration of misoprostol to nonselective NSAIDs may be considered while paying attention to adverse GI events including diarrhea. Otherwise, co-administration of H2RA to NSAIDs may be chosen even though its PU-preventive effect is relatively low.
Strength of recommendation: strong for, level of evidence: low
Expert opinion: completely agree (33%), mostly agree (46%), partially agree (21%), mostly disagree (0%), completely disagree (0%), not sure (0%)
Benefit: preventive effect on PU and its complications
Harm: increase of antibiotic-resistant
Two studies showed the effect of
In summary,
Strength of recommendation: strong for, level of evidence: moderate
Expert opinion: completely agree (44%), mostly agree (48%), partially agree (4%), mostly disagree (4%), completely disagree (0%), not sure (0%)
Benefit: preventive effect on PU and its complications
Harm: potential adverse events of long-term PPI use (i.e., fracture, pneumonia,
Effects of PPI on prevention of recurrent PU and its complications in patients who require long-term use of LDA (75–325 mg/day) have been reported in a total of seven RCTs (Supplementary Fig. 18).105-111 A meta-analysis of the seven RCTs included 5,181 patients (3,112 patients with concomitant aspirin and PPI use; 2,069 patients with aspirin alone or aspirin with control drug), and the duration of treatment ranged from 12 to 72 weeks. The concomitant use of PPIs and aspirin compared with the control group reduced the occurrence PU by 83% (HR, 0.17; 95% CI, 0.12 to 0.25; p<0.00001) (Supplementary Fig. 19A), with risk difference of –0.13 (95% CI, –0.1 to –0.08; p<0.00001), and number needed to treat (NNT) of 7.7 (Supplementary Fig. 19B). In the subgroup analysis of patients with GU (Supplementary Fig. 20), DU (Supplementary Fig. 21), and ulcer bleeding (Supplementary Fig. 22), concomitant PPI and aspirin use compared with control groups reduced the incidence of GU, DU, and ulcer bleeding by 78% (HR, 0.22; 95% CI, 0.13 to 0.35; p<0.00001), 91% (HR, 0.09; 95% CI, 0.03 to 0.25; p<0.00001), and 83% (HR, 0.17; 95% CI, 0.07 to 0.45; p<0.0004), respectively, and the risk difference was –0.11 (95% CI, –0.16 to –0.06; p<0.0001, NNT of 9.1), –0.04 (95% CI, –0.06 to –0.02; p<0.0001, NNT of 25), and –0.03 (95% CI, –0.08 to –0.01; p<0.10), respectively. In summary, PPI reduced the recurrence of PU and bleeding in patients requiring long-term use of LDA.
However, concomitant use of PPIs in all patients taking aspirin with a history of PU should be evaluated clinically, considering the benefits and risks of long-term administration. The studies included in the meta-analysis defined PUs as mucosal injuries or defects of 3 mm or more, suggesting that a significant number of patients with erosive or mild PUs that were not clinically significant were included in the study. In addition, Lai
Grade of recommendation: strong, Level of evidence: moderate
Experts’ opinion: completely agree (74%), mostly agree (26%), partially agree (0%), mostly disagree (0%), completely disagree (0%), not sure (0%)
Benefit: effect on reducing major cardiovascular death
Harm: risk of rebleeding
There is very limited evidence in the literature to guide proper timing of restarting antiplatelet agents in patients with PU bleeding who were taking antiplatelet agents. There was only one RCT that evaluated the risk of rebleeding and adverse cardiovascular and cerebrovascular events according to continuing or stopping aspirin in patients who were taking LDA when they developed PU bleeding (Supplementary Fig. 23).112 This study compared stopping aspirin for 8 weeks and restarting aspirin after endoscopic hemostasis in patients who were taking LDA for established cardiovascular or cerebrovascular diseases. In their findings, continuing aspirin showed a nonsignificant 2-fold increased risk of recurrent ulcer bleeding within 30 days as compared with stopping aspirin (aspirin group 10.3% vs placebo group 5.4%; absolute difference [95% CI], 4.9% points [–3.6 to 13.4]). However, continuation of aspirin significantly reduced all-cause mortality rates at 8 weeks (aspirin group 1.3% vs placebo group 12.9%; absolute difference [95% CI], 11.6% points [3.7 to 19.5]), which were mainly caused by cardiovascular, cerebrovascular, or GI events. It was necessary to downgrade the level of evidence to moderate with regard to inconsistency and imprecision because there was only one study. However, the recommendation grade was high because reduction in the risk of death and a key outcome, was significantly greater.
The Japanese Society of Gastroenterology (JSGE) and the American Society for Gastrointestinal Endoscopy (ASGE) also recommended reintroduction of aspirin immediately after hemostasis is achieved.14,113 In an exception to this, the European Society of Gastrointestinal Endoscopy (ESGE) recommended to withhold aspirin for 3 days in patients with high risk of PU bleeding (active bleeding, visible vessels, or adherent clots),114 because most recurrent bleeding with continuing aspirin developed within 3 days in the abovementioned study.112 Therefore, it is recommended that aspirin should be resumed immediately after endoscopic hemostasis in patients who need long-term maintenance of aspirin because of major cardiovascular disease.
No RCT was found to guide the timing of resumption of thienopyridine including clopidogrel or dual antiplatelet therapy following PU bleeding. Therefore, the recommendation on this was made similar to the recommendation on aspirin, an area of uncertainty which needs to be revised when further research is published in this regard (Table 4).
Grade of recommendation: strong, Level of evidence: very low
Experts’ opinion: completely agree (67%), mostly agree (29%), partially agree (4%), mostly disagree (0%), completely disagree (0%), not sure (0%)
Benefit: effect on reducing thromboembolism and mortality
Harm: risk of rebleeding
There is little evidence on when and how to restart the anticoagulant after PU bleeding in patients taking anticoagulants, and previous guidelines mentioned this issue based on expert opinion (Supplementary Fig. 24). ASGE,113 ESGE114 and Asian-Pacific guideline115 recommend that resumption of anticoagulant should be made multidisciplinary access by comprehensively considering patient’s status, importance of anticoagulant treatment, characteristics of hemorrhagic ulcer lesions, effective hemostasis, and risk of rebleeding. Cardiologists assess the thromboembolic risk in patients with atrial fibrillation and deep vein thrombosis, and endoscopists assess the rebleeding risk in GI tract. In principle, we recommended restarting anticoagulants immediately after effective hemostasis of ulcer in patients with PU bleeding who need long-term use of anticoagulants, if the risk of rebleeding is low.
Currently, ESGE114 and Asia-Pacific guideline115 recommend the use of vitamin K in patients with warfarin-related severe PU bleeding for antagonistic effects to warfarin. A previous retrospective study about the optimal timing of warfarin after endoscopic hemostasis of PU showed that rapid resumption of warfarin significantly reduced the thromboembolic risk.116 The risk of thrombosis should be assessed for each patient in order to determine the appropriate timing of resumption. Several previous retrospective studies which included patients with various thromboembolic risks117,118 showed that thrombosis and mortality were reduced without increasing the risk of rebleeding if warfarin was restarted within 7 to 30 days, however, rebleeding risk increased twice if it was started within 7 days after index bleeding. The Asian-Pacific guideline115 recommends restarting warfarin with heparin bridge therapy within 3 days of endoscopic hemostasis in high thromboembolic risk group, especially because it would take time to achieve sufficient anticoagulative effect if patients with warfarin use were given antagonists (Table 5).115,119,120 ESGE guideline114 states that resumption of warfarin should be individualized and recommends restarting warfarin between 7 to 15 days after index bleeding if possible, however, it does not mention anything with regard to heparin bridge therapy.114 Asian-Pacific guideline115 recommends intravenous administration of unfractionated heparin rather than low-molecular-weight heparin for heparin bridge therapy, because unfractionated heparin has a short half-life (1 to 2 hours) after intravenous administration, and it can be stopped quickly if rebleeding occurs.
The use of direct oral anticoagulants (DOAC) in patients with PU bleeding may be differently assessed based on the severity of bleeding, time taken till the last dose of DOAC, renal function and pharmacokinetic characteristics of a given drug. The Asian-Pacific guideline115 recommends temporally withholding the use of DOAC in patients with DOAC-related upper GI bleeding considering its short half-life. Vitamin K is not recommended due to absence of antagonistic effect for DOAC. Activated charcoals are considered in patients with unstable vital signs due to severe bleeding, if not more than 3 hours after taking DOAC because plasma concentrations of DOAC reach their maximum after 3 hours of administration. Idarucizumab is considered in patients with dabigatran-related severe bleeding. It is not common for patients taking DOAC to require antagonist, and clinicians can continue conservative management while waiting for the anticoagulant effect to disappear in most patients. ASGE,113 ESGE114 and British Society of Gastroenterology (BSG) and ESGE guideline121 does not specifically recommend the optimal timing of resumption of DOAC after endoscopic hemostasis, and Asian-Pacific guideline115 recommends restarting DOAC as soon as possible, within 3 days after discontinuation. The residual anticoagulant effect in the body decreases to a minimum within 3 days of discontinuation of DOAC due to its short half-life (12 hours) except in patients with decreased renal function. In terms of heparin bridge therapy till resumption of DOAC, Asian-Pacific guideline117 does not recommend the bridge therapy considering the rapid time of action of DOAC (1 to 4 hours), while ESGE guideline114 recommends bridge therapy with unfractionated heparin or low-molecular-weight heparin rather than immediate use of therapeutic dose of DOAC, then restarting the therapeutic dose of DOAC after disappearance of rebleeding risk.
In summary, evidence about optimal timing and method of resumption of anticoagulants in patients with PU bleeding during long-term use of anticoagulants are severely lacking, however, we recommend restarting anticoagulants as soon as possible immediately following endoscopic hemostasis of PU bleeding for patients who need long-term anticoagulant therapy. The optimal timing and details of restarting are determined by comprehensively considering patients’ rebleeding risk, type and pharmacokinetic characteristics of given anticoagulants, and thromboembolic risk (Table 6).115,122,123
Strength of recommendation: weak for, level of evidence: low
Expert opinion: completely agree (38%), mostly agree (46%), partially agree (16%), mostly disagree (0%), completely disagree (0%), not sure (0%)
Benefit: preventive effect on upper GI hemorrhage
Hazard: low drug adherence, potential adverse events of long-term PPI use (e.g., fracture, pneumonia,
Six nested case-control or cohort studies (three case-control124-126 and three cohort studies127-129) which evaluated the protective effect of acid suppressants against anticoagulant-related GI hemorrhage were identified through the systematic review (Supplementary Fig. 25). PPI had a protective effect against upper GI hemorrhage in patients on dicumarinics (RR, 0.56; 95% CI, 0.38 to 0.83;
However, the H2RA did not show the same effect (RR, 0.97; 95% CI, 0.52 to 1.81;
Although findings in the meta-analyses suggested the protective effect of PPIs for the development of dicumarinic-related upper GI hemorrhage, this effect was attenuated by or limited due to the high baseline risk of GI injury found consistently in the enrolled studies.124,126,128,129 Moreover, less potent inhibition of gastric acid by H2RA showed a nonsignificant protective effect, suggesting that baseline ulcerogenic properties (preexistent erosion or ulcers on the upper GI tract,
Only two studies were included in the analysis of acid suppressants on dabigatran-related GI bleeding.127,128 It was impossible to differentiate the location of GI hemorrhage (upper vs lower) and type of acid suppressants (PPI vs H2RA). Acid suppressants did not have a protective effect against GI hemorrhage in patients on dabigatran (HR, 0.78; 95% CI, 0.44 to 1.37;
Interactions from co-administration of PPIs and oral factor Xa inhibitors (xabans) does not appear to be of significant concern based on previous studies.131,134,135 However, the interaction of PPIs and the direct thrombin inhibitor dabigatran was reported (low on-treatment level of dabigatran) from recently published studies.136-138 Potential adverse events related to the long-term use of PPIs is another concern. Therefore, balancing the risk-benefit approach is still necessary before the co-prescription of anticoagulants and acid suppressants.
Based on the evidence above, we suggest high-risk patients who are taking anticoagulants to be administered PPIs to prevent upper GI hemorrhage. In cases with PPI and warfarin co-administration, close monitoring of prothrombin time with dose adjustment is needed. In terms of DOAC, little is known about risk and benefit of PPI co-administration. Considering the number of enrolled studies in this systematic review is small and all the studies were conducted in a retrospective manner, strength of recommendation is weak and the level of evidence is low. In the absence of randomized trials demonstrating a lack of bias, solid conclusions cannot be drawn.
The incidence of drug-related PU and its complications are expected to continue to increase due to the aging of the domestic population and the increase in prevalence of major comorbidities, which will not only seriously threaten the health of elderly patients, but also increase the mortality rate, and likely result in huge costs in medical expenses nationwide.139 Therefore, publishing and disseminating the appropriate clinical practice guidelines for patients with drug-related PU is an extremely valuable task, not only in terms of medical development but also in the pursuit of social public interest through health promotion. In the future, it will be necessary to perform additional major literature searches to better define the characteristics and optimal management of drug-related PU, and revise clinical practice guidelines to keep pace with the rapidly changing medical environment.
These guidelines are being co-published on the
We would like to express deep thanks to Manager Eun Ju Lee (Medical Library of Korea University), Doctor Myung Han Hyun (Korea University Guro Hospital), Manager Na-Jin Kim and Seung-Jae Lee (Medical Library of Catholic University Songeui Campus), who initially searched the literature by each key clinical question for systematic review; Professor Gwang Ho Baik (Department of Internal Medicine, Hallym University College of Medicine) and Kee Don Choi (Department of Internal Medicine, University of Ulsan College of Medicine), who reviewed the draft manuscript and advised through peer review, and Doctor Hyun Jung Kim (Korea University College of Medicine) and Ein Soon Shin (Research Institute for Healthcare Policy, Korean Medical Association), who gave lectures and advice at the clinic guideline workshop and reviewed and corrected the methodology of the draft recommendations.
No potential conflict of interest relevant to this article was reported.
Data analysis and writing - original draft: M.K.J, C.H.P., J.S.K., J.M.P., J.Y.A., B.E.L., J.H.L., H.J.Y., Y.K.C., C.S.B., B.J.K., H.K.J., B.W.K. Study design: H.K.J., B.W.K., Y.C.L. Writing - review and editing: M.K.J., C.H.P., H.K.J., B.W.K., Y.C.L. Advice on the study design: H.K.J., B.W.K., Y.C.L. Statistical support and data acquisition: H.K.J., B.W.K. All authors have read and approved the manuscript.
Table 1 Strength of Recommendation
Strength of recommendation | Interpretation |
---|---|
Strong for | The benefit of the intervention is greater than the harm and the level of evidence is high, which is strongly recommended in most clinical situations. |
Weak for | The benefit of the intervention may vary depending on the clinical situation of the intervention or the patient/social value, and is recommended to be used selectively or conditionally. |
Strong against | The harm of the intervention is greater than the benefit and the level of evidence is high or the size of effectiveness is unclear and the level of evidence is low, which is recommended not to be used. |
Weak against | The harm of the intervention may vary depending on the clinical situation of the intervention or the patient/social value, and is recommended not to be used selectively or conditionally. |
Insufficient | Evidence to judge the size of effectiveness of the intervention or the level of evidence is insufficient, and it is not possible to decide whether or not to recommend until further research evidence is accumulated. |
Table 2 Level of Evidence
Quality level | Interpretation |
---|---|
High | We are very confident that the true effect lies close to that of the estimate of the effect. |
Moderate | We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. |
Low | Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. |
Very low | We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect. |
Table 3 Recommendations Regarding NSAID Use According to the Risk of NSAID-Induced Ulcer and Cardiovascular Disease
Risk of NSAID-induced ulcer or complication | |||
Low | High | ||
- Old age | |||
- Peptic ulcer history | |||
- Use of high dose of NSAID | |||
- Concomitant use of aspirin, antiplatelet agent, anticoagulant, or steroid | |||
Risk of cardiovascular disease | Low | Use nonselective COX inhibitors | (1) Use selective COX-2 inhibitors, or |
(2) Add proton pump inhibitors to nonselective COX inhibitors | |||
High* | Add proton pump inhibitors to nonselective COX inhibitors | (1) Avoid NSAIDs, if possible | |
(2) Add proton pump inhibitors to nonselective COX inhibitors, if NSAIDs cannot be stopped |
NSAID, nonsteroidal anti-inflammatory drug; COX, cyclooxygenase.
*Aspirin, antiplatelet agent, or anticoagulant users for the prevention of serious cardiovascular events.
Table 4 Recommendation Regarding Restarting Antiplatelet Agents According to the Medicine Classification
Patents | Antiplatelet agents | Recommendation | Level of recommendation | Level of evidence |
---|---|---|---|---|
Antiplatelet use for secondary prophylaxis of known cardiovascular disease | Aspirin | Restart after endoscopic hemostasis | Strong | High |
Other agents (e.g. P2Y12 receptor inhibitor) | Restart after endoscopic hemostasis | Strong | Low | |
Dual antiplatelet therapy (DAPT) | Restart aspirin after endoscopic hemostasis. | Strong | Low |
Table 5 Indications for Heparin Bridging for the Temporary Discontinuation of Warfarin113
Non-valvular atrial fibrillation with a CHA2DS2-VASc score >5* |
Metallic mitral valve |
Prosthetic valve with atrial fibrillation |
<3 Months after venous thromboembolism |
Severe thrombophilia (protein C or protein S deficiency, antiphospholipid syndrome) |
*CHA2DS2-VASc, congestive heart failure (1 point), hypertension (1 point), age ≥75 years (2 points), diabetes mellitus (1 point), stroke, transient ischemic attack, or thromboembolism (2 points), vascular disease (1 point), age 65–74 years (1 point), female sex (1 point).117,118
Table 6 Thrombotic Risk According to Cardiac Events113
Thrombotic risk category | Cardiac events |
---|---|
Very high | ACS or PCI <6 weeks |
High | ACS or PCI 6 weeks to 6 months ago |
Moderate to low | ACS or PCI >6 months ago; stable coronary artery disease |
New-generation drug-eluting stents and bare-metal stents carry similar thrombotic risks. The risk is highest within the first 6 weeks after PCI. The risk remains high from 6 weeks to 6 months, then remains constant thereafter.120,121
ACS, acute coronary syndrome; PCI, percutaneous coronary intervention.