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Effectiveness of Acid Suppressants and Other Mucoprotective Agents In www.nature.com/scientificreports OPEN Efectiveness of acid suppressants and other mucoprotective agents in reducing the risk of occult Received: 27 April 2018 Accepted: 31 July 2019 gastrointestinal bleeding in Published: xx xx xxxx nonsteroidal anti-infammatory drug users Tae Jun Kim1, Eun Ran Kim1, Sung Noh Hong 1, Young-Ho Kim1, Yeong Chan Lee 2, Hye Seung Kim 3, Kyunga Kim3 & Dong Kyung Chang1 Acid suppressants such as histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) are efective in preventing gastrointestinal (GI) bleeding in nonsteroidal anti-infammatory drugs (NSAIDs) users. Despite widespread acid suppressant use, there remain concerns about several potential risks of long-term use. Therefore, we investigated whether gastroprotective agents (GPAs) other than acid suppression therapy are efective in preventing NSAID-related GI injury. To this end, we studied 9,133 patients with osteoarthritis or rheumatoid arthritis who used NSAIDs for ≥1 month. A decrease of 2 g/dL or more in the hemoglobin level was considered a GI injury indicator. The GPAs included acid suppressants and other mucoprotective agents. Acid suppressants included PPIs and H2RAs. Other mucoprotective agents included misoprostol, rebamipide, and eupatilin. During a median follow-up period of 27 (range, 4.3-51.3) weeks, occult GI bleeding occurred in 1,191 (13%) patients. A comparison of patients who used GPAs concomitantly with that of nonusers in a multivariable analysis revealed the hazard ratios (HRs; 95% confdence intervals [CIs]) for occult GI bleeding were 0.30 (0.20-0.44), 0.35 (0.29-0.43), 0.47 (0.23-0.95), 0.43 (0.35-0.51), and 0.98 (0.86-1.12) for PPIs, H2RAs, misoprostol, rebamipide, and eupatilin, respectively. Compared to PPI co-treatment, H2RA, misoprostol, rebamipide, and eupatilin co-treatments were associated with occult GI bleeding HRs (95% CIs) of 1.19 (0.79-1.79), 1.58 (0.72-3.46), 1.44 (0.96-2.16), and 3.25 (2.21-4.77), respectively. Our fndings suggest that mucoprotective agents, such as rebamipide and misoprostol, as well as acid suppressants, are efective in reducing the risk for GI injury in NSAID users. Nonsteroidal anti-infammatory drugs (NSAIDs) are one of the most widely prescribed drugs worldwide because of their analgesic, anti-infammatory, and antipyretic efects. However, despite the various benefts and good efcacy of NSAIDs, their use can lead to mucosal injury of the gastrointestinal (GI) tract including GI bleeding or perforation. Te incidence of clinically signifcant upper GI bleeding in NSAID users has been estimated at 1-2.5/100 person-years1,2. Current evidence suggests that in addition to causing upper GI bleeding, NSAIDs increase the risk of lower GI bleeding to a similar extent as that of upper GI bleeding3–5. 1Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 2Department of Digital Health, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University School of Medicine, Seoul, South Korea. 3Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Correspondence and requests for materials should be addressed to K.K. (email: [email protected]) or D.K.C. (email: dkchang@ skku.edu) SCIENTIFIC REPORTS | (2019) 9:11696 | https://doi.org/10.1038/s41598-019-48173-6 1 www.nature.com/scientificreports/ www.nature.com/scientificreports Total Monotherapy of NSAID plus (N = 9,133) NSAID (N = 2,668) GPA (N = 6,465) P value Age, years 54.2 ± 14.7 55.7 ± 13.6 53.7 ± 15 <0.001 Male 3,145 (34.4) 915 (34.3) 2,230 (34.5) 0.879 BMI (kg/m2) 26.8 ± 4.7 27.7 ± 4.6 26.4 ± 4.5 0.121 Creatinine (mg/dl) 0.7 ± 0.46 0.7 ± 0.5 0.8 ± 0.4 <0.001 Co-morbidity Hypertension 1,133 (12.4) 325 (12.2) 808 (12.5) 0.456 Diabetes mellitus 273 (3) 99 (3.7) 174 (2.7) 0.011 Cerebrovascular disease 103 (1.1) 32 (1.2) 71 (1.1) 0.759 Ischemic heart disease 246 (2.7) 64 (2.4) 182 (2.8) 0.295 Concomitant GPAs None 2,668 (29.2) 2,668 (100) 0 PPI 498 (5.5) 0 498 (7.7) H2RA 1,654 (18.1) 0 1,654 (25.6) Misoprostol 85 (0.9) 0 85 (1.3) Rebamipide 1,509 (16.5) 0 1,509 (23.3) Eupatilin 2,719 (29.8) 0 2,719 (42.1) Table 1. Baseline characteristics of study participants according to GPA use. Values are expressed as means ± standard deviation or percentages. Substantial evidence has indicated that the concomitant use of gastroprotective agents (GPAs) in chronic NSAID users can reduce the risk of upper GI bleeding6,7. Tus, many practice guidelines recommend using GPAs in NSAID users with a high risk of GI bleeding8–10. However, the treatment and prevention of NSAID-associated lower GI bleeding remain unclear and difcult, because the pathogenic mechanisms are diferent and not well understood. GPAs mainly include acid suppressants, such as proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs), which primarily have a protective efect against upper GI damage. GPAs other than acid suppressants, including misoprostol, rebamipide, and eupatilin, have a diferent GI tract–protec- tive mechanism. Further, in some studies, misoprostol and rebamipide were reported to be efective against NSAID-associated enteropathy; however, the underlying mechanisms remain unclear11–13. A decrease of ≥2 g/dL in the hemoglobin level has been suggested as a clinically-relevant indicator of GI mucosal damage and has previously been evaluated as an endpoint of GI bleeding in several studies14–18. Tus, a ≥ 2 g/dL drop in the hemoglobin level could be a potential marker for NSAID-induced mucosal damage throughout the GI tract, including both upper and lower GI events. Recently, a prospective study of 84 aspirin users showed that misoprostol was superior to placebo in treat- ing small bowel ulcers complicated by small bowel ulcer bleeding in aspirin users19. Another prospective study of 104 patients who were taking low-dose aspirin or an NSAID, demonstrated that misoprostol was efective for the treatment of small bowel ulcers and erosions20. Further, two prospective studies of 80 patients and 20 patients who were taking NSAIDs reported that rebamipide showed signifcantly higher efcacy than that of pla- cebo in preventing NSAID-induced small bowel mucosal injury11,21. However, to the best of our knowledge, no large-scale study has evaluated the risk for GI bleeding in NSAID users with the concomitant use of a GPA, espe- cially rebamipide or misoprostol. Terefore, we conducted a large cohort study to determine the risk of overall GI bleeding in NSAID users by using diferent GPA co-treatments. Furthermore, we investigated whether GPAs other than PPIs or H2RAs are efective in preventing NSAID-associated occult GI bleeding. Results A total of 6,465 GPA plus NSAID users and 2,668 NSAID users without GPA were included in this study. Te most frequent GPA used was eupatilin (29.8%), followed by H2RAs (18.1%), rebamipide (16.5%), PPI (5.5%), and misoprostol (0.9%). Te mean (standard deviation) age of the 9,133 study participants was 54.2 (14.7) years. Te baseline characteristics of the participants according to concomitant GPA use are shown in Table 1. Te propor- tions of male and female patients were comparable in both groups. Patients without GPA co-treatment were more likely to be older, and to have diabetes and lower levels of creatinine compared to those with GPA co-treatment. Te proportions of comorbidities such as hypertension, cerebrovascular disease, and ischemic heart disease were comparable between both groups. During the median follow-up of 5.7 months (interquartile range, 2.0-9.8 months), occult GI bleeding devel- oped in 1,191 (13%) patients. Of the 1,191 patients with occult bleeding, 82 had endoscopically-confrmed GI bleeding. Sixty-fve patients had upper GI bleeding and 17 had lower GI bleeding. Among those with upper GI bleeding, the most cause of the bleeding was peptic ulcer (54 cases). Lower GI bleeding was noted in seven patients with angiodysplasia, six patients with ulcers, and four patients with diverticular bleeding. Figure 1A shows the Kaplan-Meier curves of the proportion of patients who developed occult GI bleeding during the 12-month study, according to concomitant GPA use. Te incident cases (%) of occult GI bleeding in each group were 703 (10.9%) in the GPA co-treatment group and 488 (18.3%) in the no-GPA co-treatment group (P < 0.001). Te comparison of concomitant GPA users with nonusers by using the multivariable Cox proportional hazard SCIENTIFIC REPORTS | (2019) 9:11696 | https://doi.org/10.1038/s41598-019-48173-6 2 www.nature.com/scientificreports/ www.nature.com/scientificreports Figure 1. (A) Cumulative incidence rate for occult gastrointestinal bleeding between NSAID monotherapy and GPA co-therapy, (B) Cumulative incidence rate for occult gastrointestinal bleeding according to each drug combinations. Multivariable analysis HR 95% CI P value Age, years 1.04 1.03-1.05 <0.001 Male 0.89 0.79-1.02 0.095 BMI (kg/m2) 1.00 1.00-1.01 0.067 Creatinine (mg/dl) 1.01 0.88-1.16 0.877 Co-morbidity Hypertension 1.04 0.87-1.24 0.634 Diabetes mellitus 1.12 0.83-1.51 0.454 Cerebrovascular disease 1.90 1.22-2.97 0.005 Ischemic heart disease 1.61 1.20-2.14 0.001 Concomitant any GPAs use 0.63 0.56-0.71 <0.001 Table 2.
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