Reviewer's report
Title:The Zelnorm Epidemiologic Study (ZEST): A Cohort Study Evaluating
Incidence of Abdominal and Pelvic Surgery related to Tegaserod Treatment
Version: 2Date:22 August 2012
Reviewer: Jeffery Anderson
Reviewer's report:
ZEST is a cohort study evaluating incidence of abdominal and pelvic surgery
related to tegaserod treatment for IBS or chronic constipation during 2002-03.
2,762 tegaserod initiators were propensity matched to 2,762 comparators and
followed for 6 months. Tegaserod did not increase gallbladder surgery and
decreased abdominal or pelvic surgery. Overall, Methods are quite thorough and
results seem consistent. Tegaserod subsequently has received restricted market
access in the US but is still marketed in other countries, and other 5HT-4 agonist
drugs are in development, justifying interest in this compound. Also, subsequent
epidemiologic studies have not confirmed an increased CV risk, which was the
basis for its market restrictions.
Essential revisions:
Results, page 10, para 1, last sentence and Table 2: I am unable to document in
Table 2 that "occurrence of claims was similar". Do you mean Table 1? Also, in
Table 2, the Hazard Ratios for abdominal surgery risk factors appear to use
non-RF subjects as comparators rather than "tegaserod vs comparator" as stated
in the Table footnote for superscript 3, which is provided for the whole column.
Also, for gender, age, the comparators do not appear to be "tegaserod vs
comparator". Please correct.
Results, para 2-3, pp 10-11. Clarify which determination of surgical events was
used as primary; confirmed by case review or not refuted or all or other? Clarify
in Methods and Discussion which denominator was used in each case and which
tegaserod group as numerator.
Tables 2-5: Clarify the comparators for surgical risk factors (as well as age,
gender, see above as well).
Discretionary revisions:
Clarify in introduction or early in Methods the time frame of the analysis and the
market (i.e., US) and relation to date of market restriction by FDA and the
geographic and epidemiologic characteristics of the database.
Page 7, para 2/3: list or reference to a table at this point the specific features
chosen to match on in propensity scoring.
Methods could be tightened, shortened, without loss of content; indeed, greater
detail on adjusted variables could be provided as noted above. Also, clarify which
surgical event rate analysis was primary and, similarly, which tegaserod use
category was primary.
In Discussion and Conclusions, shouldn't the data be interpreted to show a
reduction (rather than simply no increase) in rate of abdominal or pelvic surgery?
Why might that be? (e.g., tegaserod by relieving IBS/constipation sx also
decreases disease progression or need for more aggressive/surgical therapy?)
In Discussion, page 13, para 1, isn't another possibility for recent use HR
increase a true drug "rebound" effect?
In Discussion, page 17, para 1, is a cause of apparent increase in prior reports of
increased surgeries poor validation?
Level of interest: An article of outstanding merit and interest in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
No financial conflicts of interest currently, anticipated in future, or for 5 years.
However, note that I authored reference 8 (tegaserod and CV outcomes study).
Reviewer's report
Title:The Zelnorm Epidemiologic Study (ZEST): A Cohort Study Evaluating
Incidence of Abdominal and Pelvic Surgery related to Tegaserod Treatment
Version: 2Date:22 August 2012
Reviewer: Jeffery Anderson
Reviewer's report:
ZEST is a cohort study evaluating incidence of abdominal and pelvic surgery
related to tegaserod treatment for IBS or chronic constipation during 2002-03.
2,762 tegaserod initiators were propensity matched to 2,762 comparators and
followed for 6 months. Tegaserod did not increase gallbladder surgery and
decreased abdominal or pelvic surgery. Overall, Methods are quite thorough and
results seem consistent. Tegaserod subsequently has received restricted market
access in the US but is still marketed in other countries, and other 5HT-4 agonist
drugs are in development, justifying interest in this compound. Also, subsequent
epidemiologic studies have not confirmed an increased CV risk, which was the
basis for its market restrictions.
Essential revisions:
Results, page 10, para 1, last sentence and Table 2: I am unable to document in
Table 2 that "occurrence of claims was similar". Do you mean Table 1? Also, in
Table 2, the Hazard Ratios for abdominal surgery risk factors appear to use
non-RF subjects as comparators rather than "tegaserod vs comparator" as stated
in the Table footnote for superscript 3, which is provided for the whole column.
Also, for gender, age, the comparators do not appear to be "tegaserod vs
comparator". Please correct.
Results, para 2-3, pp 10-11. Clarify which determination of surgical events was
used as primary; confirmed by case review or not refuted or all or other? Clarify
in Methods and Discussion which denominator was used in each case and which
tegaserod group as numerator.
Tables 2-5: Clarify the comparators for surgical risk factors (as well as age,
gender, see above as well).
Discretionary revisions:
Clarify in introduction or early in Methods the time frame of the analysis and the
market (i.e., US) and relation to date of market restriction by FDA and the
geographic and epidemiologic characteristics of the database.
Page 7, para 2/3: list or reference to a table at this point the specific features
chosen to match on in propensity scoring.
Methods could be tightened, shortened, without loss of content; indeed, greater
detail on adjusted variables could be provided as noted above. Also, clarify which
surgical event rate analysis was primary and, similarly, which tegaserod use
category was primary.
In Discussion and Conclusions, shouldn't the data be interpreted to show a
reduction (rather than simply no increase) in rate of abdominal or pelvic surgery?
Why might that be? (e.g., tegaserod by relieving IBS/constipation sx also
decreases disease progression or need for more aggressive/surgical therapy?)
In Discussion, page 13, para 1, isn't another possibility for recent use HR
increase a true drug "rebound" effect?
In Discussion, page 17, para 1, is a cause of apparent increase in prior reports of
increased surgeries poor validation?
Level of interest: An article of outstanding merit and interest in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
No financial conflicts of interest currently, anticipated in future, or for 5 years.
However, note that I authored reference 8 (tegaserod and CV outcomes study).
Please review this paper.
user
Reviewer's report
Title:The Zelnorm Epidemiologic Study (ZEST): A Cohort Study Evaluating
Incidence of Abdominal and Pelvic Surgery related to Tegaserod Treatment
Version: 2Date:22 August 2012
Reviewer: Jeffery Anderson
Reviewer's report:
ZEST is a cohort study evaluating incidence of abdominal and pelvic surgery
related to tegaserod treatment for IBS or chronic constipation during 2002-03.
2,762 tegaserod initiators were propensity matched to 2,762 comparators and
followed for 6 months. Tegaserod did not increase gallbladder surgery and
decreased abdominal or pelvic surgery. Overall, Methods are quite thorough and
results seem consistent. Tegaserod subsequently has received restricted market
access in the US but is still marketed in other countries, and other 5HT-4 agonist
drugs are in development, justifying interest in this compound. Also, subsequent
epidemiologic studies have not confirmed an increased CV risk, which was the
basis for its market restrictions.
Essential revisions:
Results, page 10, para 1, last sentence and Table 2: I am unable to document in
Table 2 that "occurrence of claims was similar". Do you mean Table 1? Also, in
Table 2, the Hazard Ratios for abdominal surgery risk factors appear to use
non-RF subjects as comparators rather than "tegaserod vs comparator" as stated
in the Table footnote for superscript 3, which is provided for the whole column.
Also, for gender, age, the comparators do not appear to be "tegaserod vs
comparator". Please correct.
Results, para 2-3, pp 10-11. Clarify which determination of surgical events was
used as primary; confirmed by case review or not refuted or all or other? Clarify
in Methods and Discussion which denominator was used in each case and which
tegaserod group as numerator.
Tables 2-5: Clarify the comparators for surgical risk factors (as well as age,
gender, see above as well).
Discretionary revisions:
Clarify in introduction or early in Methods the time frame of the analysis and the
market (i.e., US) and relation to date of market restriction by FDA and the
geographic and epidemiologic characteristics of the database.
Page 7, para 2/3: list or reference to a table at this point the specific features
chosen to match on in propensity scoring.
Methods could be tightened, shortened, without loss of content; indeed, greater
detail on adjusted variables could be provided as noted above. Also, clarify which
surgical event rate analysis was primary and, similarly, which tegaserod use
category was primary.
In Discussion and Conclusions, shouldn't the data be interpreted to show a
reduction (rather than simply no increase) in rate of abdominal or pelvic surgery?
Why might that be? (e.g., tegaserod by relieving IBS/constipation sx also
decreases disease progression or need for more aggressive/surgical therapy?)
In Discussion, page 13, para 1, isn't another possibility for recent use HR
increase a true drug "rebound" effect?
In Discussion, page 17, para 1, is a cause of apparent increase in prior reports of
increased surgeries poor validation?
Level of interest: An article of outstanding merit and interest in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
No financial conflicts of interest currently, anticipated in future, or for 5 years.
However, note that I authored reference 8 (tegaserod and CV outcomes study).
assistant