Point by point response
Dear Editor:
Thank you for your kind letter to encourage us to re-submit our revised manuscript to your journal.
The comments of two reviewers have been helpful in allowing us to revise our manuscript. We have
attempted to address the questions raised by the referees according to the following:
Reviewer #1
Major Revisions
1. Why were trials where protease inhibitors given oral, intra-arterial or via intra-abdominal
infusions excluded? Certainly the title of the paper does not suggest that the method of giving
anti-protease therapy would be a limiting factors. The authors need to explain the reasons and also
modify the title accordingly.
2. Why was the administration of FFP an exclusion factor?
Thank you very much for your comments. As indicated, protease inhibitors have been used to treat
mild to severe pancreatitis including post-ERCP pancreatitis in various ways. We are concerned that
assessment including all modalities might veil the potential difference of effectiveness among these
modalities and dilute the results. Among these modalities, our primary interest is the effectiveness of
intravenous administration of protease inhibitors to treat pancreatitis excluding post-ERCP ones that
we previously conducted a meta-analysis. The reason we evaluated the effectiveness of protease
inhibitors given intravenous infusion was that the main theme of this study was an update the body
of evidence on the effectiveness of intravenous use of protease inhibitors for acute pancreatitis.
Besides, we described another reasons we excluded studies of protease inhibitors given oral,
intra-arterial or intra-abdominal infusion or FFP administration in “Discussion”. And, we decided
our article’s title, “Treatment of acute pancreatitis with protease inhibitors given intravenous
infusion: an updated systematic review and meta-analysis.”
3. Also exclusion criteria 11 seems very global and could introduce bias. The authors need to clarify
which papers were removed due to this exclusion criteria and why?
Evaluating the true effectiveness of protease inhibitors given intravenous infusion, we thought that
mixing different participants’ backgrounds were inappropriate. Therefore, we excluded except
intravenous infusion studies. In reality, no article was excluded by the criteria 11. We are afraid
that this criterion may give a wrong impression, so we deleted it in the revised manuscript.
4. One of the problems with studies in acute pancreatitis is that each RCT uses differing definitions
of severity. This leads to misclassification of patients into mild, moderate or severe pancreatitis and
makes any meta-analysis difficult. How did the authors deal with this problem? How many different
definitions of severity were used in the 17 RCTs?
First, the definition of acute pancreatitis has not been standardized throughout the target period for
the present review, so the review included trials that used different definitions. Second, the severity
of acute pancreatitis should be evaluated based on Ranson’s score or APACHE-Ⅱ. In the present
review, only two RCTs used these scoring systems [34, 49]. We conducted alternative sub-group
analyses by control mortality rate (CMR) and found that meta-analysis of studies with CMR>0.20
showed that protease inhibitors were an effective. However, we recognize that CMR was determined
at the end of trials, so-called as a “retrospective index”, and that it is not sufficiently validated to
interpret CMR as a surrogate of severity of acute pancreatitis. According to the comments, we
deleted the expressions in the method that CMR was used as a surrogate of severity. In the
discussion, we added descriptions of the possibilities and limitations to regard CMR as a surrogate of
severity of patients included in each trial as follows: As an advantage, CMR can retrospectively
calculate with ease. However, CMR has these demerits: 1) CMR cannot accurately evaluate a
severity of acute pancreatitis; and 2) The validity of CMR is insufficient. In present study, we
reluctantly used CMR as a surrogate of severity because the only two RCTs used the Ranson’s score
or APACHE-Ⅱ score [34, 49].
5. Outcome measures should be separated into primary and secondary.
According to your comment, we described the primary or secondary outcome of each randomized
controlled trial in Method and Result session and Tables.
The following outcomes were employed to measure the effectiveness of protease inhibitors for acute
pancreatitis: the primary outcome as 1) death due to acute pancreatitis; and the secondary outcomes
as 2) relief from pain; 3) pseudocyst formation; 4) formation of intra-abdominal abscess; 5) surgical
intervention; 6) paralytic small bowel obstruction; and 7) any other major complications including
multiple organ failure.
6. GRADE – it was mentioned in the letter but where is the analysis? It would be nice to know how
the body of evidence stacks up in terms of quality.
We evaluated quality of each RCT with GRADE system. We described these results in Table 2.
Furthermore, we showed body of evidence for each outcome with high, moderate, low, or very low
in Table 3 and the Result session.
7. Not enough is made of the fact that protease therapy did reduce mortality with low heterogeneity
in the subgroup of patients with severe acute pancreatitis. This needs to be discussed further. Perhaps
antiprotease therapy is indicated in this subgroup of patients? A Forest plot would be helpful for this
subgroup analysis.
We found two RCTs [34, 49] to treat severe acute pancreatitis that was assessed before the treatment.
Trapnell’s study [34] was a multicenter RCT (placebo versus Trasylol). The definition of acute
pancreatitis was based on abnormal imaging and high value of serum amylase (greater than 1000
Somogyi units). Chen’s study [49] was a single-center RCT (placebo versus Gabexate mesilate). The
definition of acute pancreatitis was based on Ranson’s score and APACHE-Ⅱincluding abnormal
imaging, high value of serum amylase (three times greater than normal value), and abdominal pain.
The meta-analysis of these two studies showed the significant effectiveness of protease inhibitors for
acute severe pancreatitis. However, it was difficult to determine the true effectiveness because low
quality of RCTs and high risk of bias were yielded very heterogeneous results between the two
studies. We have to wait for further research on the issue.
Upon your comment, we added a forest plot of acute severe pancreatitis (Figure 3).
8. The conclusion is nihilistic. There is recent animal research showing that perhaps targeting
anti-proteases to mesenteric lymph may be a way forward. Certainly, there should be a paragraph in
the discussion about where to from here? New directions in research should be discussed rather than
shutting the door forever on this type of therapy.
According to your comments, we rewrote the“Conclusion”.
We thought the true effectiveness of protease inhibitor was insufficient or unknown. However, the
protease inhibitors might still have the positive effectiveness for severe acute pancreatitis, we
rewrote the discussion.
Reviewer #2
Minor Revisions
As you pointed out, we collected some spellings. Besides we rewrote the last paragraph of the
discussion.
The detailed reviews of our manuscript are deeply appreciated and we hope we have adequately
responded each of the critiques raised. We are looking forward hearing from you again.
Thank you very much for your consideration in this matter.
Sincerely yours,
SETA Takeshi, M.D.
NOGUCHI Yoshinori, M.D., M.P.H.
SHIKATA Satoru, M.D., Ph. D.
NAKAYAMA Takeo, M.D., Ph. D.