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Choe Y, Park JM, Kim JS, Cho YK, Kim BW, Choi MG, Kim NJ. Drugs Effective for Nonsteroidal Anti-inflammatory Drugs or Aspirin-induced Small Bowel Injuries: A Systematic Review and Meta-analysis of Randomized Controlled Trials. J Clin Gastroenterol 2024; 58:1003-1010. [PMID: 39008569 DOI: 10.1097/mcg.0000000000001975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 01/02/2024] [Indexed: 07/17/2024]
Abstract
OBJECTIVE The frequency of small bowel (SB) injuries has increased due to the increased use of nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin. This study was a systematic review and meta-analysis to compare drugs effective for SB injuries caused by NSAIDs or aspirin use. METHODS We searched MEDLINE, Embase, and Cochrane registries for randomized controlled trials through February 2023. The extracted data included changes in the number of erosions or ulcers in the jejunum or ileum observed through capsule endoscopy in patients taking NSAIDs or aspirin and administration of various mucoprotectants. We investigated the therapeutic or preventive efficacy of these drugs. The methodological bias was evaluated using Risk of Bias 2.0. RESULTS Eighteen randomized controlled trials of drugs effective for NSAIDs or aspirin-induced SB injuries were included and analyzed. The agents used to treat or prevent SB injuries were rebamipide, misoprostol, geranylgeranylacetone, and probiotics. In the meta-analysis, the mucoprotectants that showed a significant effect in treating NSAID users, who developed SB injuries, were misoprostol (mean difference: -9.88; 95% CI: -13.26 to -6.50). Meanwhile, the mucoprotectant that can prevent SB injuries caused by NSAIDs or aspirin in the general population was rebamipide (mean difference: -1.85; 95% CI: -2.74 to -0.96). CONCLUSIONS Misoprostol was effective in treating SB injuries caused by NSAIDs or aspirin (CRD42023410946).
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Affiliation(s)
- Younghee Choe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jae Myung Park
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Catholic Photomedicine Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Joon Sung Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yu Kyung Cho
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Byung-Wook Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Myung-Gyu Choi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Catholic Photomedicine Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Na Jin Kim
- Medical Library, The Catholic University of Korea, Seoul, Republic of Korea
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Teutsch B, Boros E, Váncsa S, Váradi A, Frim L, Kiss S, Dembrovszky F, Helyes Z, Patrícia S, Péter H, Erőss B. Mucoprotective drugs can prevent and treat nonsteroidal anti-inflammatory drug-induced small bowel enteropathy: a systematic review and meta-analysis of randomized controlled trials. Therap Adv Gastroenterol 2021; 14:17562848211038772. [PMID: 34616487 PMCID: PMC8488515 DOI: 10.1177/17562848211038772] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 07/06/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Small bowel enteropathy (SBE) is a complication of nonsteroidal anti-inflammatory drug (NSAID) therapy occurring in 71% of NSAID users. We aimed to analyse the efficacy and safety of medications to prevent and treat NSAID-induced SBE in randomized controlled trials (RCTs). METHODS This review was registered on PROSPERO (CRD42021223371). We systematically searched four databases until 20 October for comparing mucoprotective (MP), antibiotic and probiotic treatments to placebo, proton-pump inhibitors (PPIs) or histamine-2 (H2) receptor antagonists in NSAID-associated small intestinal injuries. The main outcomes were mucosal integrity, mucosal breaks after treatment, mucosal injury improvement and complete healing of mucosal breaks. Meta-analytical calculations for weighted mean differences (WMDs) and odds ratios (ORs) were performed with the random-effects model and interpreted with 95% confidence intervals (CIs). RESULTS A total of 18 RCTs were included in the quantitative synthesis. MP medications administered preventively reduced the number of mucosal erosions (WMD = -1.24, CI: -2.15 to -0.34) and lead to a significantly lower chance of developing mucosal breaks after treatment (OR = 0.38, CI: 0.16-0.93). MP therapy was associated with a higher rate of complete healing of mucosal breaks (OR = 5.39, CI: 2.79-10.42). In the qualitative synthesis, there were tendencies for a lower increase in the mean number of mucosal breaks and reddened lesions with prophylactic and a higher decrease in mucosal breaks with therapeutic MP drug administration. CONCLUSION MP treatment administered with NSAIDs can prevent and reduce small intestinal mucosal lesions.
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Affiliation(s)
- Brigitta Teutsch
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Eszter Boros
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Division of Gastroenterology, Fejér County Szent György University Teaching Hospital, Székesfehérvár, Hungary
| | - Szilárd Váncsa
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Alex Váradi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Levente Frim
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Szabolcs Kiss
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
| | - Fanni Dembrovszky
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Zsuzsanna Helyes
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary
| | - Sarlós Patrícia
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Hegyi Péter
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Bálint Erőss
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Szigeti Street 12, Pécs 7624, Hungary
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
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Drapkina OM, Korneeva ON. [Small bowel injuries due to nonsteroidal anti-inflammatory drugs and antiplatelet therapy. Approaches to prevention and treatment]. TERAPEVT ARKH 2016. [PMID: 28635889 DOI: 10.17116/terarkh20168812133-139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Nonsteroidal anti-inflammatory drug (NSAID)-induced small bowel injuries (NSAID enteropathies) become clinically important. Videocapsule endoscopy shows that the small bowel is involved in NSAID-related gastrointestinal tract (GIT) injury in almost two-thirds of all cases. Due to a large number of patients who receive NSAIDs, combined antiplatelet therapy, or long use anticoagulants, GIT injury prevention becomes an actual problem. Treatment for NSAID enteropathy is different from that for NSAID gastropathy. In NSAID enteropathy, it is advisable to use drugs that are able to increase the production of prostaglandins and mucus, to restore intestinal epithelial permeability, and to exert anti-inflammatory and antioxidant effects. Rebamipide that produces many pleiotropic effects and also has cytoprotective properties may become the drug of choice for treating patients with NSAID enteropathy. In addition, rebamipide has no effects on various cytochrome P-450 enzyme systems, by reducing the risk of drug interactions.
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Affiliation(s)
- O M Drapkina
- National Research Center for Preventive Medicine, Ministry of Health of Russia, Moscow, Russia
| | - O N Korneeva
- National Research Center for Preventive Medicine, Ministry of Health of Russia, Moscow, Russia
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Zhang S, Qing Q, Bai Y, Mao H, Zhu W, Chen Q, Zhang Y, Chen Y. Rebamipide helps defend against nonsteroidal anti-inflammatory drugs induced gastroenteropathy: a systematic review and meta-analysis. Dig Dis Sci 2013; 58:1991-2000. [PMID: 23456504 DOI: 10.1007/s10620-013-2606-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Accepted: 02/14/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) has been perplexing most clinicians and users of NSAIDs. Rebamipide is increasingly advocated as a candidate option for the prevention of NSAIDs induced gastrointestinal mucosal injury. AIMS To assess the efficacy and the safety of rebamipide for the prevention and treatment of NSAID-induced gastroenteropathy. METHODS PubMed, Embase, Web of Science, Google Scholar, the Cochrane Library, Japan Science and Technology Information Aggregator, and China Biology Medicine Disc were searched up to December 2011. Randomized controlled trials (RCTs) recruiting subjects with co-prescriptions of NSAIDs and rebamipide were eligible. Efficacy and safety of rebamipide were reevaluated, and dichotomous data were pooled to obtain relative risk (RR) with a 95 % confidence interval. Heterogeneity and publication bias were assessed by the inconsistency index statistic and funnel plot analysis, respectively. RESULTS The search identified 338 citations, and 15 RCTs including 965 individuals were eligible. In general, rebamipide acted better than placebo against short-term NSAID-induced gastroduodenal injury. Separate studies showed rebamipide was equal to or not superior to traditional strategies (including PPIs, H2RA and misoprostol treatment). Especially, rebamipide showed a beneficial effect against the small bowel damage (total RR = 2.70, 95 % confidence interval = 1.02-7.16, P = 0.045) when compared with placebo group. The average incidence of adverse events was about 36.1 % (0-70.0 %) but no serious event was recorded. CONCLUSIONS Current evidences show rebamipide is effective and safe for defending against NSAID-induced gastroduodenal and lower-gastrointestinal injuries. However, more well-designed trials should be conducted to fully confirm the practical value of rebamipide.
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Affiliation(s)
- Shaoheng Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou North Avenue, Baiyun District, Guangzhou 510515, China
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Mizukami K, Murakami K, Hirashita Y, Hisamatsu A, Ogawa R, Uchida M, Nakagawa Y, Okimoto T, Kodama M, Fujioka T. Efficacy of rebamipide for low-dose aspirin-related gastrointestinal symptoms. J Clin Biochem Nutr 2012. [PMID: 23170050 DOI: 10.3164/jcbn.12.27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Gastrointestinal symptoms are a problematic issue for patients who take low-dose aspirin for long time. We conducted a pilot study to investigate the efficacy of combination therapy with proton pump inhibitor and rebamipide. This was a prospective, randomized, double-blind, placebo-controlled cross-over study. All the subjects received aspirin 100 mg and omeprazole 20 mg. The subjects were divided into two groups and received either rebamipide 300 mg or placebo, which was prescribed for 4 weeks. The subjects were instructed to record their gastrointestinal symptom rating scale before the study and 1 and 4 weeks after beginning the protocol. These scores of the groups were compared before and after the treatment to evaluate the severity of their symptoms and the number of symptom items present in each group. For the subjects receiving rebamipide, the total prevalence of lower gastrointestinal symptoms was significantly different from the placebo group (p=0.0093) at week 4. No troublesome symptoms were observed in the rebamipide group. Inconclusion, the administration of rebamipide prevented the occurrence of troublesome symptoms, especially lower gastrointestinal symptoms, in patients taking aspirin and omeprazole. Rebamipide is a candidate drug for combination therapy with proton pump inhibitors to prevent low-dose aspirin-induced gastrointestinal symptoms.
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Affiliation(s)
- Kazuhiro Mizukami
- Departments of Gastroenterology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasamamachi, Yufu, Oita 879-5593, Japan
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Mizukami K, Murakami K, Hirashita Y, Hisamatsu A, Ogawa R, Uchida M, Nakagawa Y, Okimoto T, Kodama M, Fujioka T. Efficacy of rebamipide for low-dose aspirin-related gastrointestinal symptoms. J Clin Biochem Nutr 2012; 51:216-20. [PMID: 23170050 PMCID: PMC3491247 DOI: 10.3164/jcbn.12-27] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2012] [Accepted: 04/25/2012] [Indexed: 12/27/2022] Open
Abstract
Gastrointestinal symptoms are a problematic issue for patients who take low-dose aspirin for long time. We conducted a pilot study to investigate the efficacy of combination therapy with proton pump inhibitor and rebamipide. This was a prospective, randomized, double-blind, placebo-controlled cross-over study. All the subjects received aspirin 100 mg and omeprazole 20 mg. The subjects were divided into two groups and received either rebamipide 300 mg or placebo, which was prescribed for 4 weeks. The subjects were instructed to record their gastrointestinal symptom rating scale before the study and 1 and 4 weeks after beginning the protocol. These scores of the groups were compared before and after the treatment to evaluate the severity of their symptoms and the number of symptom items present in each group. For the subjects receiving rebamipide, the total prevalence of lower gastrointestinal symptoms was significantly different from the placebo group (p=0.0093) at week 4. No troublesome symptoms were observed in the rebamipide group. Inconclusion, the administration of rebamipide prevented the occurrence of troublesome symptoms, especially lower gastrointestinal symptoms, in patients taking aspirin and omeprazole. Rebamipide is a candidate drug for combination therapy with proton pump inhibitors to prevent low-dose aspirin-induced gastrointestinal symptoms.
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Affiliation(s)
- Kazuhiro Mizukami
- Departments of Gastroenterology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasamamachi, Yufu, Oita 879-5593, Japan
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Zhu LL, Xu LC, Chen Y, Zhou Q, Zeng S. Poor awareness of preventing aspirin-induced gastrointestinal injury with combined protective medications. World J Gastroenterol 2012; 18:3167-72. [PMID: 22791953 PMCID: PMC3386331 DOI: 10.3748/wjg.v18.i24.3167] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Revised: 05/02/2012] [Accepted: 05/05/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate prescribing pattern in low-dose aspirin users and physician awareness of preventing aspirin-induced gastrointestinal (GI) injury with combined protective medications.
METHODS: A retrospective drug utilization study was conducted in the 2nd Affiliated Hospital, School of Medicine, Zhejiang University. The hospital has 2300 beds and 2.5 million outpatient visits annually. Data mining was performed on all aspirin prescriptions for outpatients and emergency patients admitted in 2011. Concomitant use of proton-pump inhibitors (PPIs), histamine 2-receptor antagonists (H2RA) and mucoprotective drugs (MPs) were analyzed. A defined daily dose (DDD) methodology was applied to each MP. A further investigation was performed in aspirin users on combination use of GI injurious medicines [non-steoid anti-inflammatory drugs (NSAIDs), corticosteroids and clopidogrel and warfarin] or intestinal protective drugs (misoprostol, rebamipide, teprenone and gefarnate). Data of major bleeding episodes were derived from medical records and adverse drug reaction monitoring records. The annual incidence of major GI bleeding due to low-dose aspirin was estimated for outpatients.
RESULTS: Prescriptions for aspirin users receiving PPIs, H2RA and MPs (n = 1039) accounted for only 3.46% of total aspirin prescriptions (n = 30 015). The ratios of coadministration of aspirin/PPI, aspirin/H2RA, aspirin/MP and aspirin/PPI/MP to the total aspirin prescriptions were 2.82%, 0.12%, 0.40% and 0.12%, respectively. No statistically significant difference was observed in age between patients not receiving any GI protective medications and patients receiving PPIs, H2RA or MPs. The combined medication of aspirin and PPI was used more frequently than that of aspirin and MPs (2.82% vs 0.40%, P < 0.05) and aspirin/H2RA (2.82% vs 0.12%, P < 0.05). The values of DDDs of MPs in descending order were as follows: gefarnate, hydrotalcite > teprenone > sucralfate oral suspension > L-glutamine and sodium gualenate granules > rebamipide > sucralfate chewable tablets. The ratio of MP plus aspirin prescriptions to the total MP prescriptions was as follows: rebamipide (0.47%), teprenone (0.91%), L-glutamine and sodium gualenate granules (0.92%), gefarnate (0.31%), hydrotalcite (1.00%) and sucralfate oral suspension (0.13%). Percentages of prescriptions containing aspirin and intestinal protective drugs among the total aspirin prescriptions were: rebamipide (0.010%), PPI/rebamipide (0.027%), teprenone (0.11%), PPI/teprenone (0.037%), gefarnate (0.017%), and PPI/gefarnate (0.013%). No prescriptions were found containing coadministration of aspirin and other NSAIDs. Among the 3196 prescriptions containing aspirin/clopidogrel, 3088 (96.6%) prescriptions did not contain any GI protective medicines. Of the 389 prescriptions containing aspirin/corticosteroids, 236 (60.7%) contained no GI protective medicines. None of the prescriptions using aspirin/warfarin (n = 22) contained GI protective medicines. Thirty-five patients were admitted to this hospital in 2011 because of acute hemorrhage of upper digestive tract induced by low-dose aspirin. The annual incidence rates of major GI bleeding were estimated at 0.25% for outpatients taking aspirin and 0.5% for outpatients taking aspirin/warfarin, respectively.
CONCLUSION: The prescribing pattern of low-dose aspirin revealed a poor awareness of preventing GI injury with combined protective medications. Actions should be taken to address this issue.
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