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PEER REVIEW HISTORY
BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to
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are provided with free text boxes to elaborate on their assessment. These free text comments are
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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.
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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
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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
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