Responses II to reviewer's report / Luca Ansaloni
Title: A prospective randomized controlled multicenter trial comparing antibiotic
therapy (ertapenem) with appendectomy in the treatment of uncomplicated acute
appendicitis (APPAC trial)
Version: 2
Reviewer: Luca Ansaloni
Reviewer's report:
Major Compulsory Revisions
1) Pag 3 Section Background Par 3 Row 1
Luca Ansaloni reply: I agree with the authors’ revision.
Liu et al in their review and meta-analysis affirm that “CT was not uniformly used
for the diagnosis in any of the studies, which likely resembles the real situation
and the most of the rest of the world. Because the diagnostic approach was
similar between the antibiotics-treated and appendectomy groups, the lack of CT
scans in making the diagnosis is unlikely to have had any impact on the results”.
(Liu, K. and L. Fogg, Use of antibiotics alone for treatment of uncomplicated
acute appendicitis: a systematic review and meta-analysis. Surgery, 2011.
150(4): p. 673-83.)
The rarity in the use of CT scan has some consequence on the usefulness of the
present study:
- the results will be no comparable with the vast majority of previous study but
theoretically only to Vons study.
- Due to the worldwide parsimonious use of CT scan for AA there is the risk that
the results cannot be comparable to future studies and furthermore the
reproducibility of the model in common clinical practice could be compromised.
The aim of the APPAC study as stated on page 4, second paragraph: “The overall
objective of the study is to provide level I evidence to support the hypothesis that
approximately 75 - 85 % of patients with uncomplicated AA can be treated without surgery
by using effective antibiotic therapy.” With this study aim, the use of CT scan for
diagnosing uncomplicated acute appendicitis will prevent bias in our result as also the
antibiotic group patients are also treated for acute appendicitis enabling accurate
comparison with the surgery group. In this respect, this diagnosis confirmation was
necessary with the best diagnostic tool available. It is clear that CT scan is not available
worldwide to diagnose acute appendicitis and our study is not focusing on CT diagnosis
but on the non-operative treatment of uncomplicated acute appendicitis.
Luca Ansaloni reply: despite the authors reply is a formally correct however, I would like,
one more time, underline that the role of CT scan in the diagnosis is very limited, due to
the very limited use of CT scan for patient with suspicion of AA. As a consequence the
reproducibility of the model in common clinical practice could be compromised. I suggest
the authors to underline that CT scan was routinely used only for research proposal.
Author reply: The information on the use of CT scan for research purposes was
added (the added text underlined) in the manuscript as follows on page 3, last
paragraph.
“Abdominal computed tomography (CT) is the best non-invasive diagnostic tool
available and it has become more commonly used in this respect for patients with
AA with a high sensitivity and specificity [19, 20]. Most previous RCTs comparing
antibiotic therapy with surgery in the management of AA are lacking abdominal CT
to confirm AA [13-16]. Therefore, a well-designed controlled trial comparing nonoperative management versus early appendectomy for uncomplicated AA
corroborated by CT imaging has been called for [8]. CT scan is used in the APPAC
trial for research purposes as CT scan confirmed uncomplicated acute appendicitis
will prevent bias in our result as the antibiotic group patients are also treated for
acute appendicitis enabling accurate comparison with the surgery group. The only
previous study of antibiotic treatment in CT scan diagnosed AA indicated that
amoxicillin/clavulanic acid was not non-inferior to emergency appendectomy in the
treatment of AA, but identification of predictive markers, such as appendicolith, on
CT scans might enable improved targeting of antibiotic treatment [17]….”
2) Pag 6 Section Participants Sub-section Exclusion criteria
Luca Ansaloni reply: I agree to the author’s observation.
3) Pag 7 Section Interventions Sub-section Antibiotic therapy Par 1 row 2
Luca Ansaloni reply: I agree with the author’s revision.
The objective method of patient evaluation in our opinion after the randomization needs to
be clinical as a new CT scan to rule out complicated appendicitis in the antibiotic group
would be unethical and the treatment decision could not be based solely on the CT
findings. The decision to proceed to surgical treatment needs to be clinical in order to
ensure patient safety. Some of the antibiotic group patients will have uncomplicated
appendicitis at surgery and the operative findings will be thoroughly recorded to evaluate
the actual treatment success.
The APPAC study is conducted in central or university hospitals in the surgical emergency
setting and thus the clinical re-evaluation (always performed by surgeons) is of more
importance than specific cut-off values for laboratory tests or fever etc. as they are taken
into account in the clinical evaluation performed by the surgeon on call.
Luca Ansaloni reply: I disagree with the absence of author’s revision of this point.
The authors define unethical a second CT scan: I completely agree to this sentence but, at
the mean time, I suggest the authors to express their consideration on the routine use of
CT scan as proposed in the study (see also comment 1).
Author reply: Please see reply to comment 1, the information on research use of CT
has been added. Our manuscript/ APPAC-trial does not propose the routine use of
CT scan and this was not a study end-point as it was used for AA diagnosis.
Furthermore I solicit the authors to define the clinical suspicion at “central or university
hospitals”. As I already stressed there is a lack in worldwide accepted diagnostic criteria
for AA and the clinical suspicion seems not enough as a criteria comparing to the well
defined diagnostic criteria of the majority of disease.
The authors in their study protocol use the “clinical suspicion” at least two times: one time
at the selection of patients eligible for CT scan and secondarily in case of suspected
antibiotic failure; in order to avoid already known criticism, I stress the authors to use some
clinical score available.
Alternatively I suggest, in order to prevent criticisms, to well define it, in the discussion
section, as a weak point of the paper.
Author reply: We strongly agree with the reviewer that the lack of worldwide
accepted criteria for the clinical suspicion of AA is a problem, which is yet to be
solved as the available scoring systems have not gained popularity in clinical
practise as their sensitivity and specificity are suboptimal. We wanted the results of
this multicenter randomized trial to be applicable to current clinical practise
evaluating the AA diagnosis mainly based on clinical practise and using the
“clinical suspicion of AA” as an evaluation for enrollment enables the generalization
of the trial results. We understand the evaluation of the reviewer regarding the
possible weak point of our study. On the other hand, we feel that the reproducibility
of the model in common clinical practise presents a strong element of the trial.
This enrollment evaluation of “clinical suspicion of AA” will also provide us with
prospective information on the sensitivity and specificity regarding expert clinical
diagnosis of AA as all of the patients undergoing a CT scan were evaluated for AA
suspicion in a surgical emergency setting instead of, for example, being evaluated
by general practitioners.
4) Pag 7 Section Interventions Sub-section Antibiotic therapy Par 1 row 6
In case of ertapenem allergy (known or newly diagnosed), the intravenous
antibiotic treatment will consist of tazobactam 4 g x 3 combined with
metronidazole 500 mg x 3. The three- day intravenous antibiotic treatment will be
followed by seven days of oral antibiotic therapy with levofloxacin 500 mg x 1
combined with metronidatzole 500 mg x 3 resulting in ten-day total duration of
the antibiotic therapy. In case of allergy for fluoroquinolones (known or newly
diagnosed), levofloxacin will be replaced either with cefalexin 500 mg x 3 or
clindamycin 400 mg x 3.
The use of such different antibiotic regimens strongly expose the study to failure.
The population study size was calculated to compare only two treatment options:
the analysis of subgroups, according to antibiotic regimens, will not reach
statistical significance. At the opposite the Authors attempt to present all the
antibiotic regimens as equivalent treatments cannot be approved. I finally
suggest to exclude patients with allergy to primary antibiotic regimen
(Ertapenem) or to remodelling the population study.
For patients with Ertapenem allergy, we needed to have an alternative antibiotic treatment,
but this will not expose the study to failure as there are only few patients with this allergy.
The small number of these patients will not present bias in the antibiotic group and this is
in addition also supported by the fact that all of these regimens cover approximately the
same bacterial flora. This is also true for the per oral antibiotic treatment.
Luca Ansaloni reply: I disagree to the author’s revision.
As authors said “all of these regimens cover approximately the same bacterial flora” so
they are not the same. Because the regimens are not the same I suggest to exclude from
the study the “few patients with this allergy”.
If your intention is to include in the study patients treated with different antibiotics you
should avoid, in the title as well in the body of the paper, to affirm the comparison of
surgery to Ertapenem.
Author reply: We thank the reviewer for pointing out this controversy regarding the
antibiotic treatment. The aim of our study is not focused on ertapenem but antibiotic
treatment (with ertapenem) and we have thus altered the title leaving the word
ertapenem out “A prospective randomized controlled multicenter trial comparing
antibiotic therapy with appendectomy in the treatment of uncomplicated acute
appendicitis (APPAC trial)”. This will also be taken into account in analyzing the
data as we at least need to perform separate analysis with the ertapenem patients
and ertapenem + possible other antibiotics used.
5) Pag 8 Section Outcome Parameters Sub-section The primary endpoint Par 1
The primary endpoint of treatment success in this non-inferiority trial is defined in
the antibiotic treatment arm as the resolution of AA with antibiotic treatment
resulting in discharge from the hospital without the need for surgical intervention
and no recurrent appendicitis during a minimum follow-up of one-year (treatment
efficacy). Treatment efficacy in the operative treatment arm is defined as
successful appendectomy evaluated to be 100 %.
I’m aware of the intrinsic difficulty to define common outcome for both arms;
however the Authors choice to differentiate the primary endpoint between groups
could leads to partial success of the study.
The primary success of antibiotic treatment is evaluated along one year while the
primary success of surgical treatment is evaluated exclusively at the mean time
of the operation. What about, at least, intraoperative complications? In the
antibiotic arm the need for surgery into one year is a failure: way the need for a
new operation, related to appendectomy, in the surgical group into one year is
not a failure?
According to my meta-analysis and “Regarding these study designs, particular
attention should be made to identify a clear and concise definition of efficacy to
be used for both the conservative and surgical treatments, standardizing the
different treatment procedures as much as possible”. (Ansaloni, L., F. Catena, F.
Coccolini, G. Ercolani, F. Gazzotti, E. Pasqualini, and A.D. Pinna, Surgery versus
conservative antibiotic treatment in acute appendicitis: a systematic review and
meta-analysis of randomized controlled trials. Dig Surg, 2011. 28(3): p. 210-21.)
Also the Authors agree with this sentence in the discussion section (Pag 15 row
3)
In our opinion, the primary endpoint of our APPAC study is common in both groups as it is
the success of the randomized treatment = resolution of appendicitis. As the treatments
are very different from each other, the evaluation cannot be performed at the same time
point. If the definition of success in the antibiotic group would not take recurrent
appendicitis into account, this would bias the results of the trial falsely favoring antibiotic
treatment. For the surgical treatment the success rate is naturally 100 % from a surgical
point-of-view - “no appendix, no appendicitis”. In our opinion, operative complications
cannot be compared with recurrence and all of these other factors are evaluated as
secondary endpoints as is stated in the text on page 3, third paragraph: “Secondary
endpoints are post-intervention complications, overall morbidity and mortality, the length of
hospital stay and sick leave, treatment costs and pain VAS-scores.” This definition will
naturally include possible reoperations after appendicectomy, for example incisional hernia
repair (overall morbidity).
Luca Ansaloni reply : I disagree to the author’s reply.
I’m aware of the intrinsic difficulty to define common outcome for both arms. However, in
my opinion, the sentence “no appendix, no appendicitis” doesn’t fully answer my revision.
In my opinion, we cannot define as surgical success the removal of the appendix in case
of some complication requiring re-intervention.
I suggest to insert the difficulty to compare antibiotic and surgery in the discussion section.
Author reply: The following sentence was altered to stress this difficulty, alteration
underlined (discussion section, page 16 first paragraph): “Regarding these study
designs, particular attention should be made to identify a clear and concise
definition of efficacy to be used for both the conservative and surgical treatments,
standardizing the different treatment procedures as much as possible [6-8] even
though there is an intrinsic difficulty in defining a common outcome for both
treatment arms. “
6) Pag 8 Section Outcome Parameters Sub-section The primary endpoint Par 1
Row 4
Treatment efficacy in the operative treatment arm is defined as successful
appendectomy evaluated to be 100 %.
A more exhaustive definition of this primary endpoint is needed: does the Authors
mean without intraoperative complications?
All of the complications (intra- and postoperative) are secondary outcomes and thoroughly
recorded, please see our response to comment 5.
Luca Ansaloni reply: please see number 5
Author reply: Please see reply to comment 5.
7) Pag 8 Section Outcome Parameters Sub-section Secondary endpoints Par 1
Row 1
A recurrent AA will be diagnosed on a clinical basis.
Please see comment above (number 3).
Please see our response to comment 3.
Luca Ansaloni reply: please see number 3
Author reply: Please see reply to comment 3.
8) Pag 10 Section Outcome Parameters Sub-section Intervention data-Antibiotic
therapy Row 4
Possible cross-over to operative treatment and the clinical symptoms
necessitating emergency appendectomy
Please see comment above (number 3)
Please see our response to comment 3.
Luca Ansaloni reply: please see number 3
Author reply: Please see reply to comment 3.
Minor Essential Revisions
No comments to be done.
Discretionary Revisions
1) Pag 3 Section Background Par 3 Row 5
Luca Ansaloni: any comment
2) Pag 5 Section Participants Par 2 Row 7
If clinical history and physical examination suggest that the patient has
uncomplicated AA, the patient is eligible for inclusion in the APPAC study and the
patients are informed of the protocol and invited to participate. After signed
informed consent is obtained, a CT scan will be performed to confirm the
diagnosis of uncomplicated AA.
I suggest to define the criteria for clinical suspicion: the risk is to loose patients
for the study or to expose patient to no-useful CT scan radiation.
Please see our response to comment 3; the study is performed in a surgical setting at
central or university hospitals, there are no general practitioners evaluating the patients
and thus the clinical suspicion is not more clearly defined as all the doctors performing the
evaluation are surgeons or surgical residents.
Luca Ansaloni: please see comment 3
Author reply: Please see reply to comment 3.
3) Pag 6 Section Participants Sub-section Exclusion criteria Par 2 Row 8
Luca Ansaloni: any comment
4) Pag 7 Section Intervention Sub-section Surgical treatment Par 1 Row 2
Luca Ansaloni: any comment
5) Pag 7 Section Intervention Sub-section Antibiotic therapy Par 1 Row 2
Luca Ansaloni: any comment