Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Downloaded from http://bmjopen.bmj.com/ on October 18, 2016 - Published by group.bmj.com PEER REVIEW HISTORY BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below. Some articles will have been accepted based in part or entirely on reviews undertaken for other BMJ Group journals. These will be reproduced where possible. ARTICLE DETAILS TITLE (PROVISIONAL) AUTHORS Extended-Release Nifedipine and the Risk of Intestinal Obstruction: A Population-Based Study Juurlink, David; Hellings, Chelsea; Gomes, Tara; Huang, Anjie; Paterson, Michael; Urbach, David; Mamdani, Muhammad VERSION 1 - REVIEW REVIEWER REVIEW RETURNED GENERAL COMMENTS Derrick Lung University of California, San Francisco 20-Apr-2014 Introduction: I would modify the description of bowel obstruction reported in prior case reports by whether or not these were associated with therapeutic usage or not. And, also normal or abnormal anatomy needs to be discussed as a risk factor for bezoar formation. I vaguely remember at least one of the case reports being associated with therapeutic use, but not entirely certain. Obviously, therapeutic use is much different than overdose circumstances where bezoar formation is more likely. When talking about amlodipine, what does "formulation not associated with bowel obstruction" mean, exactly? It would be helpful to know what specific products and formulations are being prescribed... I assume only a few in Canada? Overally, nice study design. Well-written. Besides a few questions for clarification, I only recommend a statistician to double-check the study methods. REVIEWER REVIEW RETURNED GENERAL COMMENTS Dr Lekha Saha Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, INDIA 21-Apr-2014 The authors claimed the present as the first controlled study to explore the phenomena of intestinal obstruction with nifedipine, but the present study is a retrospective population-based cohort study. The facts are already known that nifedipine and amlodipine caused rare incidence of intestinal obstruction. Downloaded from http://bmjopen.bmj.com/ on October 18, 2016 - Published by group.bmj.com Regarding the factors associated with intestinal obstruction are so widely distributed and can not be controlled in a retrospective study like this. So from this type of study it is very difficult to comments on such type of rare side effects. The authors should clarify and discussed the following points: Sustained-release formulations of nefedipine including Procardia XL® and Adalat XL® have been mentioned here. What about other preparations like Afeditab, Nifediac etc and intestinal obstruction. Regarding the mechanism of obstruction by these formulations is mainly because of impact of the formulation in the gut and that causes mechanical obstruction. Therefore the cause of obstruction is not clear whether it is because of formulation or drug itself ? It is not very clear. The baseline characteristics of the patients that increased the risk of intestinal obstruction have not been discussed. Should discussed about other associated factors that can lead to obstruction like use of other drugs like aspirin or disease conditions like hypertension. Because all these factors can increased the risk of obstruction In the discussion the authors should also discuss their results in contrast with already published case reports or studies. Nothing new information is added by the present study. VERSION 1 – AUTHOR RESPONSE Reviewer #1 Please modify the description of bowel obstruction reported in prior case reports by whether or not these were associated with therapeutic usage or not. And, also normal or abnormal anatomy needs to be discussed as a risk factor for bezoar formation. The reviewer vaguely remembers at least one of the case reports being associated with therapeutic use, but not entirely certain. Obviously, therapeutic use is much different than overdose circumstances where bezoar formation is more likely. Response: Previous case reports describe mechanical small bowel obstruction in the setting of therapeutic use, not overdose. It is postulated that this reflects the delivery system of this popular form of long-acting nifedipine. We have revised the introduction to indicate this. When talking about amlodipine, clarify what "formulation not associated with bowel obstruction" means, exactly? Response: Unlike nifedipine, amlodipine has a long duration of action and does not require formulation in an extended-release matrix. We have clarified this in the revised manuscript (page 6), contrasting the half-lives of nifedipine (2 hours) and amlodipine (30 to 50 hours) to explain why amlodipine does not require a special formulation to allow once-daily dosing. It would be helpful to know what specific products and formulations are being prescribed. I assume only a few in Canada? Response: The Canadian product is Adalat XL and the US product is Procardia XL. We have noted this in the revised manuscript. Overall, nice study design. Well-written. Besides a few questions for clarification, I only recommend Downloaded from http://bmjopen.bmj.com/ on October 18, 2016 - Published by group.bmj.com that a statistician double-check the methods. Response: We thank the reviewer for these positive comments. Reviewer #2 The authors claimed the present as the first controlled study to explore the phenomena of intestinal obstruction with nifedipine, but the present study is a retrospective population-based cohort study. The facts are already known that nifedipine and amlodipine caused rare incidence of intestinal obstruction. Response: This is an observational study rather than a RCT. It is controlled in that amlodipine-treated patients constitute the reference group. We respectfully disagree with the reviewer’s second point; the existing literature consists of case reports of bowel obstruction involving extended-release nifedipine only. Regarding the factors associated with intestinal obstruction are so widely distributed and cannot be controlled in a retrospective study like this. So from this type of study it is very difficult to comments on such type of rare side effects. Response: The rarity of the outcome is why postmarket observational studies such as this are required. With regard to factors associated with intestinal obstruction, this is the purpose of the amlodipine reference group. Importantly, there are no appreciable imbalances in measured factors between the two groups of patients (Table 1). The authors should clarify and discuss the following points: Sustained-release formulations of nifedipine including Procardia XL® and Adalat XL® have been mentioned here. What about other preparations like Afeditab, Nifediac etc and intestinal obstruction? Response: Please see our response to the similar comment of Reviewer #1. Only Adalat XL is available in Ontario, but any risk would be shared by all forms of long-acting nifedipine that employ the proprietary Gastrointestinal Therapeutic System (GITS). Afeditab and Nifediac are not available in North America, but they appear to utilize a different delivery system and consequently may not confer the same risk. Regarding the mechanism of obstruction by these formulations is mainly because of impact of the formulation in the gut and that causes mechanical obstruction. Therefore the cause of obstruction is not clear whether it is because of formulation or drug itself? It is not very clear. Response: The association between extended-release nifedipine and bowel obstruction is to relate to the formulation (the Gastrointestinal Therapeutic System; GITS), rather than the drug itself. The GITS delivery system allows drug to seep from a small pore (the delivery orifice), while the tablet itself passes intact in the stool. Speculation exists that this tablet shell can sometimes cause mechanical bowel obstruction. This delivery system is used for other drugs, including doxazosin (see below) and atenolol Our study may therefore have relevance beyond calcium channel blockers. The baseline characteristics of the patients that increased the risk of intestinal obstruction have not been discussed. Should discussed about other associated factors that can lead to obstruction like use of other drugs like aspirin or disease conditions like hypertension. In the discussion the authors Downloaded from http://bmjopen.bmj.com/ on October 18, 2016 - Published by group.bmj.com should also discuss their results in contrast with already published case reports or studies. Response: The point of this comment is not clear. We have documented baseline characteristics for nifedipine- and amlodipine-treated patients in Table 1. Moreover, ASA use and hypertension do not cause intestinal obstruction. If we have misinterpreted this point please let us know. Downloaded from http://bmjopen.bmj.com/ on October 18, 2016 - Published by group.bmj.com Extended-release nifedipine and the risk of intestinal obstruction: a population-based study David N Juurlink, Chelsea Hellings, Tara Gomes, Anjie Huang, J Michael Paterson, David R Urbach, Muhammad M Mamdani and for the Canadian Drug Safety and Effectiveness Research Network (CDSERN) BMJ Open 2014 4: doi: 10.1136/bmjopen-2014-005377 Updated information and services can be found at: http://bmjopen.bmj.com/content/4/7/e005377 These include: References This article cites 12 articles, 4 of which you can access for free at: http://bmjopen.bmj.com/content/4/7/e005377#BIBL Open Access This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ Email alerting service Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article. Topic Collections Articles on similar topics can be found in the following collections Epidemiology (1732) Gastroenterology and hepatology (170) Notes To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/