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Rifaximin in Prevention of Intestinal Lesions Associated With Nonsteroidal Anti-Inflammatory Drugs: Good Idea Needing Confirmation
Gastroenterology 2017;-:1
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CORRESPONDENCE Readers may submit letters to the editor concerning articles that appeared in Gastroenterology within one month of publication. Detailed guidelines regarding the content are included in the Instructions to Authors.
Rifaximin in Prevention of Intestinal Lesions Associated With Nonsteroidal Anti-Inflammatory Drugs: Good Idea Needing Confirmation Dear Editors: I read with great interest the article by Scarpignato et al1 evaluating the efficacy of rifaximin in preventing intestinal lesions associated with nonsteroidal anti-inflammatory drugs (NSAIDs). The authors declare that rifaximin is effective in preventing the occurrence of NSAID-induced intestinal lesions and that intestinal bacteria contribute to the development of NSAID-associated enteropathy.1 Intestinal mucosal injury is very common in NSAID users,2 and effective treatment for NSAID-associated enteropathy is lacking to date. Thus, this preliminary study sheds new light on the prevention of NSAID-induced intestinal injury and is of great importance to clinical practice. I appreciated the great efforts done by the authors. However, when using the conclusions of this study in clinical settings, we should be cautious and several issues deserve further evaluation. First, in the supplementary materials, the study stated that “to be included in the study, VCE [video capsule endoscopy] should have shown no abnormality, but a maximum of 1 mucosal break (erosion or ulcer) in the small bowel was allowed.” This means that the healthy volunteers included in this study are not all healthy (a maximum of 1 mucosal break in the small bowel was allowed). Including patients with a mucosal break in a study of intestinal lesion prevention is not appropriate. Moreover, the diseases causing mucosal breaks in baseline are not provided in the article. The distribution of mucosal break at baseline between groups is not provided either, raising concern of selection bias. The possibility of underlying diseases affecting the occurrence of intestinal lesions could not be excluded. Selection bias of enrollment would affect the validity of the results of the study. Second, the utmost merit of this study is the randomized, controlled trial design. This method increases the likelihood of equilibrium between groups and avoids confounding factors influencing the studied end point. So the difference of age between groups should not be statistically significant. The primary endpoint (subjects developing 1 mucosal lesion) is not statistically significant (P ¼ .0566), which indicates no efficacy of rifaximin in prevention of NSAID-associated intestinal lesions. However, including age in the analysis leads to the results become significant (P ¼ .0490). This is not logical in the setting of a randomized, controlled trial. Furthermore, in undertaking regression analysis, all the confounding factors at baseline (age, gender, and drug
history) should be included. The results of regression analysis including all the factors in baseline are not provided. Thus, the analytic bias of the results is also of concern. Based on the results of the primary endpoint, rifaximin is not effective in preventing NSAID-associated intestinal lesions. Any selection analyses cannot change the conclusion drawn from the results of the primary endpoint. Third, the setting of the study is not in accordance with real clinical settings. NSAIDs are mostly taken for chronic diseases (coronary heart diseases and rheumatoid diseases), so taking NSAIDs is a long-term process. The follow-up time of this study is only 14 days. So whether rifaximin is effective in preventing NSAID-associated intestinal lesions cannot be drawn from this short period of study. Fourth, even if this study has a positive result, we cannot conclude that intestinal bacteria contribute to the development of NSAID-associated enteropathy. I read the article thoroughly, and do not find any description of the evaluation of small bowel bacterial overgrowth. Glucose breath test, lactulose breath test, and small intestinal aspiration and culture are all available.3 However, this study does not use any of these methods to evaluate for small bowel bacterial overgrowth. The effect of rifaximin on small bowel bacteria is only from inference. Thus, the evidence chain between rifaximin and small bowel bacteria is not linked. Moreover, the study declares that healthy volunteers are included in the study; small bowel bacterial overgrowth should not be present in healthy volunteers. The conclusion that intestinal bacteria contribute to the development of NSAID-associated enteropathy cannot be drawn from this study. In conclusion, this study has potential selection bias and analytic biases; clinicians should be cautious in using the conclusions of this study. More studies with larger sample size and longer follow-up are needed to evaluate the preventive effect of rifaximin on NSAID-associated intestinal lesions. Q2 ZHI-FENG ZHANG Department of Gastroenterology The First Affiliated Hospital of Dalian Medical University Dalian, Liaoning Province, China
References 1. 2. 3.
Scarpignato C, et al. Gastroenterology 2017;152: 980–982. Graham DY, et al. Clin Gastroenterol Hepatol 2005;3: 55–59. Rezaie A, et al. Curr Gastroenterol Rep 2016;18:8.
Conflicts of interest The author discloses no conflicts.
http://dx.doi.org/10.1053/j.gastro.2017.05.057
COR 5.4.0 DTD YGAST61233_proof 29 June 2017 5:56 am ce
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CORRESPONDENCE Readers may submit letters to the editor concerning articles that appeared in Gastroenterology within one month of publication. Detailed guidelines regarding the content are included in the Instructions to Authors.
Rifaximin in Prevention of Intestinal Lesions Associated With Nonsteroidal Anti-Inflammatory Drugs: Good Idea Needing Confirmation Dear Editors: I read with great interest the article by Scarpignato et al1 evaluating the efficacy of rifaximin in preventing intestinal lesions associated with nonsteroidal anti-inflammatory drugs (NSAIDs). The authors declare that rifaximin is effective in preventing the occurrence of NSAID-induced intestinal lesions and that intestinal bacteria contribute to the development of NSAID-associated enteropathy.1 Intestinal mucosal injury is very common in NSAID users,2 and effective treatment for NSAID-associated enteropathy is lacking to date. Thus, this preliminary study sheds new light on the prevention of NSAID-induced intestinal injury and is of great importance to clinical practice. I appreciated the great efforts done by the authors. However, when using the conclusions of this study in clinical settings, we should be cautious and several issues deserve further evaluation. First, in the supplementary materials, the study stated that “to be included in the study, VCE [video capsule endoscopy] should have shown no abnormality, but a maximum of 1 mucosal break (erosion or ulcer) in the small bowel was allowed.” This means that the healthy volunteers included in this study are not all healthy (a maximum of 1 mucosal break in the small bowel was allowed). Including patients with a mucosal break in a study of intestinal lesion prevention is not appropriate. Moreover, the diseases causing mucosal breaks in baseline are not provided in the article. The distribution of mucosal break at baseline between groups is not provided either, raising concern of selection bias. The possibility of underlying diseases affecting the occurrence of intestinal lesions could not be excluded. Selection bias of enrollment would affect the validity of the results of the study. Second, the utmost merit of this study is the randomized, controlled trial design. This method increases the likelihood of equilibrium between groups and avoids confounding factors influencing the studied end point. So the difference of age between groups should not be statistically significant. The primary endpoint (subjects developing 1 mucosal lesion) is not statistically significant (P ¼ .0566), which indicates no efficacy of rifaximin in prevention of NSAID-associated intestinal lesions. However, including age in the analysis leads to the results become significant (P ¼ .0490). This is not logical in the setting of a randomized, controlled trial. Furthermore, in undertaking regression analysis, all the confounding factors at baseline (age, gender, and drug
history) should be included. The results of regression analysis including all the factors in baseline are not provided. Thus, the analytic bias of the results is also of concern. Based on the results of the primary endpoint, rifaximin is not effective in preventing NSAID-associated intestinal lesions. Any selection analyses cannot change the conclusion drawn from the results of the primary endpoint. Third, the setting of the study is not in accordance with real clinical settings. NSAIDs are mostly taken for chronic diseases (coronary heart diseases and rheumatoid diseases), so taking NSAIDs is a long-term process. The follow-up time of this study is only 14 days. So whether rifaximin is effective in preventing NSAID-associated intestinal lesions cannot be drawn from this short period of study. Fourth, even if this study has a positive result, we cannot conclude that intestinal bacteria contribute to the development of NSAID-associated enteropathy. I read the article thoroughly, and do not find any description of the evaluation of small bowel bacterial overgrowth. Glucose breath test, lactulose breath test, and small intestinal aspiration and culture are all available.3 However, this study does not use any of these methods to evaluate for small bowel bacterial overgrowth. The effect of rifaximin on small bowel bacteria is only from inference. Thus, the evidence chain between rifaximin and small bowel bacteria is not linked. Moreover, the study declares that healthy volunteers are included in the study; small bowel bacterial overgrowth should not be present in healthy volunteers. The conclusion that intestinal bacteria contribute to the development of NSAID-associated enteropathy cannot be drawn from this study. In conclusion, this study has potential selection bias and analytic biases; clinicians should be cautious in using the conclusions of this study. More studies with larger sample size and longer follow-up are needed to evaluate the preventive effect of rifaximin on NSAID-associated intestinal lesions. Q2 ZHI-FENG ZHANG Department of Gastroenterology The First Affiliated Hospital of Dalian Medical University Dalian, Liaoning Province, China
References 1. 2. 3.
Scarpignato C, et al. Gastroenterology 2017;152: 980–982. Graham DY, et al. Clin Gastroenterol Hepatol 2005;3: 55–59. Rezaie A, et al. Curr Gastroenterol Rep 2016;18:8.
Conflicts of interest The author discloses no conflicts.
http://dx.doi.org/10.1053/j.gastro.2017.05.057
COR 5.4.0 DTD YGAST61233_proof 29 June 2017 5:56 am ce
Q1
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