A randomized, double-blinded, placebo-controlled, multicenter trial, healing effect of rebamipide in patients with low-dose aspirin and/or non-steroidal anti-inflammatory drug induced small bowel injury

Kurokawa, Syuhei; Katsuki, Shinichi; Fujita, Toshio; Saitoh, Yusuke; Ohta, Hidetoshi; Nishikawa, Kouji; Sato, Yasushi; Sato, Yasuhiro; Ohira, Koji; Yamada, Masataka; Kato, Mototsugu

doi:10.1007/s00535-013-0805-2

Cited by 49 publications

(39 citation statements)

References 20 publications

(27 reference statements)

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“…Many candidates medications are summarized in Table 3. Rebamipide has not only the healing effect for NSAIDs-induced enteropathy compared with placebo [37][38][39][40]. Misoprostol have a preventive effect forNSAIDinduced small intestinal mucosal injuries [40,41].…”

Section: Prevention and Therapy Of Non-steroidal Antiinflammatory Drumentioning

confidence: 99%

Non-Steroidal Anti-Inflammatory Drug (NSAID)-Induced Small Intestinal Injury

Tajima¹

2013

Pharm Anal Acta

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Section: Prevention and Therapy Of Non-steroidal Antiinflammatory Drumentioning

confidence: 99%

Non-Steroidal Anti-Inflammatory Drug (NSAID)-Induced Small Intestinal Injury

Tajima¹

2013

Pharm Anal Acta

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“…prevented LDA-induced gastric mucosal injury (i.e., erythema in the antrum) in healthy volunteers (p = 0.039) [3]. Moreover, rebamipide not only prevented LDA and NSAID-induced enteropathy, but also improved the nutritional status of the study subjects [17]. Nonetheless, it is unclear if rebamipide is useful for the prevention of gastric mucosal injuries induced by concomitant use of LDA and clopidogrel.…”

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confidence: 98%

Does Rebamipide Prevent Gastric Mucosal Injury in Patients Taking Aspirin and Clopidogrel?

2014

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The use of anti-platelet agents, such as low-dose aspirin (LDA) and clopidogrel, for primary and secondary prophylaxis against cardiovascular and cerebrovascular disease is increasing in an aging society, especially in developed countries. Moreover, since the benefits of dual anti-platelet therapy (DAT) with LDA and clopidogrel have been confirmed in the treatment or prevention of cardiovascular and cerebrovascular disease, DAT, but not monotherapy with LDA or clopidogrel, is often used in complicated patients such as after drug-eluting stent implantation, where DAT therapy is required for more than 6 months in order to avoid potentially catastrophic stent thrombosis. The efficacy of DAT for patients with a past history of cardiovascular events is well supported in the medical literature.The downside of DAT is foregut mucosal injury, which affects almost all recipients, regardless of symptoms [1][2][3]. Thus, much attention has been focused on the prevention of mucosal injury, which can manifest as severe gastrointestinal hemorrhage or perforation. Accordingly, Tozawa et al. [4] in this issue of Digestive Diseases and Sciences demonstrated that in a randomized, double-blinded, placebo-controlled trial, rebamipide, a foregut mucosal protective agent widely used in Japan, significantly inhibited gastric mucosal damage induced by LDA alone or by DAT in healthy subjects.The doses of anti-thrombotic agents are balanced between their beneficial and their adverse gastrointestinal effects, informed in part by their mechanisms of action. LDA, a platelet cyclooxygenase-1 inhibitor, not only injures the gastric mucosa, but also injures the esophageal and small bowel mucosa, even with enteric-coated formulations [2,5]. The recommended doses of aspirin for the prevention of cardiovascular and cerebrovascular disease are 75-300 mg/day, though when benefits and adverse risks are taken into account, the optimal dose of aspirin is no more than 100 mg/day [6]. A gastric mucosal damage score of [1 according to the modified Lanza criteria [7] is observed in 93 % of healthy volunteers after administration of LDA, irrespective of age and duration of therapy [2]. Nevertheless, although the detailed biological mechanism of clopidogrel-induced mucosal damage is unclear, clopidogrel is less likely than LDA to damage the foregut mucosa, which belies the observation that clopidogrel often causes massive gastrointestinal bleeding due to its potent anti-platelet effects by the inhibition of the purinergic P2Y12 receptor expressed on the platelet cell membrane [8]. This observation is supported in a separate analysis, in analyses divided modified Lanza scores into ulcer/erosion and hemorrhage scores in subjects receiving monotherapy with LDA or clopidogrel monotherapy, the former increasing both scores, yet the latter increased the hemorrhage score more than the ulcer/erosion score [1]. Using Cox proportional hazard regression analysis, monotherapy of clopidogrel increases the risk of upper gastrointestinal bleeding [hazard ratio 3.66; 95 % C...

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“…3,4,[6][7][8][9][10][11]15,[18][19][20][21][22][23][24][25][26] However, in most studies, the primary endpoint was smallbowel mucosal injury, and the outcomes did not include smallbowel overt bleeding. In addition, these studies had small sample sizes, and half of them included healthy subjects and nonhospital-based patients.…”

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confidence: 99%

“…In addition, these studies had small sample sizes, and half of them included healthy subjects and nonhospital-based patients. 6,8,9,11,15,18,19,22,23,25,26 Although two of these studies investigated patients with small-bowel overt bleeding, these were retrospectively collected data. 6,11 This is the first multicenter study to use prospectively collected data using capsule endoscopy, enabling the evaluation of two associations: (i) between drug use and small-bowel mucosal injury; and (ii) between drug use and small-bowel overt bleeding in patients with small-bowel mucosal injury.…”

mentioning

confidence: 99%

Associations between drugs and small‐bowel mucosal bleeding: Multicenter capsule‐endoscopy study

Niikura

Yamada

Maki

et al. 2017

Digestive Endoscopy

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Background and Aim: Although several drugs may induce small-bowel mucosal injuries, it is unclear whether these injuries contribute to overt small-bowel bleeding. This study was designed to evaluate the associations between drug use and small-bowel mucosal injury and between these mucosal injuries and overt bleeding in a disease-relevant population. Methods:We retrospectively studied patients with suspected small-bowel diseases who underwent capsule endoscopy between 2010 and 2013. Drug exposure, Charlson Comorbidity Index, smoking, and alcohol consumption were assessed before capsule endoscopy. Adjusted odds ratios (AOR) and confidence intervals (CI) were estimated for small-bowel mucosal injury and small-bowel overt bleeding.Results: In total, 850 patients were analyzed during the study period. Median age was 64 years, and 544 patients (64.0%) were men. Among the patients with small-bowel mucosal injury (n = 60) and without mucosal injury (n = 705), use of nonsteroidal anti-inflammatory drugs (NSAIDs) (AOR 1.8, 95% CI 1.01-3.31) was significantly associated with an increased risk of small-bowel mucosal injury compared with non-use. Patients with small-bowel mucosal injury with overt bleeding (n = 85) and without overt bleeding (n = 60) were compared, and no significant difference between the groups in the usage rates for NSAIDs, thienopyridine, other antiplatelets, anticoagulants, acetaminophen, tramadol hydrochloride, or steroids was revealed, even after adjusting for confounders. Conclusion:Although the use of NSAIDs was significantly associated with an increased risk of small-bowel mucosal injury, no significant associations were observed between the use of such drugs and small-bowel overt bleeding.

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A randomized, double-blinded, placebo-controlled, multicenter trial, healing effect of rebamipide in patients with low-dose aspirin and/or non-steroidal anti-inflammatory drug induced small bowel injury

Cited by 49 publications

References 20 publications

Non-Steroidal Anti-Inflammatory Drug (NSAID)-Induced Small Intestinal Injury

Non-Steroidal Anti-Inflammatory Drug (NSAID)-Induced Small Intestinal Injury

Does Rebamipide Prevent Gastric Mucosal Injury in Patients Taking Aspirin and Clopidogrel?

Associations between drugs and small‐bowel mucosal bleeding: Multicenter capsule‐endoscopy study

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