Review for 10.1186/s12876-023-02836-x (2023)

Title: Endoscopic injection sclerotherapy for treating recurrent bleeding of small bowel
angioectasias
Version: 1 Date: 07 Jan 2023
Reviewer's report:
Reviewer Comments:
Reviewer 1
This study is a retrospective and single-center case-control study in China to evaluate
effectiveness and safety of endoscopic injection sclerotherapy (EIS) for treating recurrent
bleeding of small bowel angioectasias (SBAs). The authors concluded that EIS could be regard
as the preferred endoscopic therapy for SBAs. This topic is interesting, but I have some
comments as indicated below.
Major comments:
1) There seems to be a bias between the control and EIS group. Especially, I am anxious
about the significant difference of age between control and EIS groups. As patients grow old,
complications might increase. There is a possibility that the difference of age affects rebleeding
rates. Could you please explain this point?
Reply: Thanks for your comments. Romagnuolo, et al. [Reference 7 in the article] reported
that there were similar comparative re-bleeding rates between patients underwent endoscopic
treatment and those received no therapy (42.7%, 95% CI: 38.0%-47.0% versus 49.2%, 95%
CI: 40.0%-58.0%); and this result suggested that no less than half of the patients could not
experience a recurrence, regardless of whether they received endoscopic treatment or not. Just
because of this, our study enrolled patients with recurrent bleeding before admission to ensure
all the participants were at high risk for recurrence. It was through this rigorous inclusion criteria
that we could adequately evaluate the effectiveness of EIS treatment. Just as you worried about,
age over 65 years was a risk factor of recurrent bleeding [Reference 1 in the article] and there was
an age bias in our study because of the small sample size. However, in this study which enrolled
patients with high risk for recurrence, univariate and multivariate analysis did not suggest age as
a significant risk factor for recurrence (Table 4 and Table 5). In order to obtain stronger evidence,
we hope organize a multi-center study with large sample to reduce the impact of biases.
#I agreed
2) Active bleeding observed in the control group chose conservative treatment. In the EIS
group, the re-bleeding rate may have decreased because the responsible lesion was identified
and treatment intervention was possible. Is there a rationale for deciding which of treatments
to choose? Because the choice can be a serious bias, the authors should have some kind of
indication. In addition, I want to know the characteristics of lesions in the control and EIS group
(e.g., type of SBAs, number of lesions, number of treated lesions, presence of active bleeding
etc.).
Reply: Thanks for your comments. This was a retrospective study and the patients were divided
into the EIS group and the control group according to whether they underwent EIS treatment.
Due to the retrospective nature of this study, we were unable to prospectively assign patients to
a treatment or control group. We found lesions with active oozing or bleeding in few patients,
and this can be associated to the prior hemostatic treatment in most patients. Most patients
with SBAs presented with chronic bleeding, which was determined by the characteristics of
these lesions. For SBB patients who were willing to receive DBE, once responsible lesions or
suspicious lesions were captured, we must treat them; and it is the basic principle and ethical
requirement of DBE to conduct examination and treatment simultaneously. For patients who
were only willing to undergo CE screening, they refused subsequent DBE procedure due to its
risk and had to passively receive conservative treatment. I guess you might worry about that
there were some lesions with brisk active bleeding under CE in our control group but we had not
treated them. Active massive hemorrhage can be a major characteristic of arterial malformations
and hemangiomas in the small bowel and these lesions always need emergency interventions.
Once responsible lesions or suspicious lesions were captured by CE, we can’t ignore them unless
the patient or the family insisted on giving up. Unfortunately, SBAs are prone to relapse even
when the responsible lesions are identified and damaged. The effectiveness on conventional
methods of endoscopic therapy for SBAs is still debated. As a result, both endoscopic therapy
and conservative treatment are reasonable options for SBAs. The physician chose the treatment
based on the guideline [1] and the patient's wishes in this study. As for characteristics of lesions,
the revised Table 1 shows the characteristics of lesions in the control and EIS group.
#I agreed
3) This study included patients with bleeding at least twice in 12 months before admission. It
should be mentioned how to deal with the first bleeding. The authors also described that the
re-bleeding rate of patients underwent EIS treatment was 22.58% (7/31). Please describe the
treatment of re-bleeding in these 7 cases.
Reply: Thanks for your comments. We appreciated your suggestion and we have added medical
history before admission in the manuscript as following:
Before admission, all patients suffered 2-6 times bleeding occurrence and 74.24% of patients
(49/66) had experienced at least 1 time of hospitalization; and most of them were referred
from other medical centers without BAE equipment. For the first episode, bleeding went into
spontaneous remission in the minority of patients, and the majority required hospitalization and
hemostatic drugs (octreotide or somatostatin) to stop bleeding. 65.15% of patients (43/66) had
experienced at least 1 time of RBC transfusion before admission. (Line 226-232) Additionally,
we have added description of treatment of re-bleeding in the EIS group in the manuscript as
following:
Octreotide or thalidomide was recommended for all patients with recurrent bleeding after
discharge, because they refused repeated endoscopic examinations of small bowel. Considering
the high cost, these patients had very low acceptance of long-term octreotide use; and they
were more inclined to the temporary use of octreotide after bleeding occurrence. Among these
patients, a 67-year-old female in the control group received long-acting octreotide therapy after
her discharge as frequent melena. In China, the use of thalidomide in the treatment of SBAs
is off-label; and it also has a lot of side effects; thus, the patient’s acceptance of long-term
thalidomide use is very low. Even so, all the patients who suffered re-bleeding were treated
properly in the follow-up. (Line 278-287)
#Well corrected
4) Let me know the progress during hospitalization? In control group, did the patients stayed
longer in the hospital because re-bleeding occurred or other events?
Reply: Thanks for your comments. We appreciated your suggestion and we have added the
corresponding content in the manuscript as following: Among the current hospitalization,
routine medical treatment according to the 2015 ACG clinical guideline [1], was performed in
all patients. The patients with present bleeding, were treated with hemostatic drug (octreotide,
Novartis Pharma AG, Switzerland), intravenous iron, transfusion of packed RBCs and so on.
For those with yellow feces or negative results of fecal occult blood, intravenous iron and
RBC transfusion were given according to the clinical needs. Patients were discharged when
they met the following criteria: (1) with yellow feces or negative results of fecal occult blood;
(2) hemoglobin levels were stable and > 7 g/dL; (3) without anemia related severe symptoms.
The post-endoscopic adverse events were recorded in detail. The lengths of stay (LOSs) were
recorded and compared between groups. (Line 173-182)
#Well corrected
5) There was comparison between EIS and APC in the discussion. It should also mention the
comparison between EIS and clip in the discussion.
Reply: Thanks for your comments. We appreciated your suggestion and we have added relevant
content in the manuscript as following:
It should be noted that there were less direct studies on the independent application of hemostatic
clips for the management of SBAs due to the risk of subsequent shedding; and this technique
might be particularly useful to treat larger angioectasias or combine with other therapies [6].
(Line 353-356)
#I agreed
6) Reference 12 is a report of the efficacy of EIS for hemangioma and is ineligible for comparison
with SBA in this paper. The authors should use the literature describing the effectiveness of
EIS for SBA.
Reply: Thanks for your comments. We appreciated your suggestion and we have cited
the following reference: Ponte A, Perez-Cuadrado Robles E, Pinho R, et al. High short-
term rebleeding rate in patients undergoing a second endoscopic therapy for small-
bowel angioectasias after recurrent bleeding. Rev Esp Enferm Dig. Feb 2018;110(2):88-93.
Additionally, we have revised relevant description as following: The re-bleeding rate of patients
underwent EIS treatment in this study was 22.58% (7/31), which was significantly lower than
that reported by previous studies employing conventional techniques such as APC, contact
cautery, and clips [7, 9, 25]. (Line 348-351)
#I agreed
7) As can be said throughout, this content shows the effectiveness of the EIS, but it does not
compare APC. Some representations could be misleading as better than APC, such as “the
rate of re-bleeding in our study was far lower than that of APC reported by Romagnuolo, et
al. [7] and Sakai, et al. [22], further indicating effectiveness of EIS to treat SBAs” (page10)
and “In EIS treatment, local submucosal injection with sclerosing agent did not cause
small bowel perforation in any case. In contrast, APC is a technique of noncontact thermal
therapy; and the close contact with intestinal wall of thermal probe could lead to perforation,
which is a life-threatening adverse event for those patients with advanced age and multiple
complications.” (Page 11). I would suggest modifying the sentence.
Reply: Thanks for your comments. We did not compare effectiveness of APC and EIS treatment
in this study. However, though enrolling patients with re-bleeding, the rate of re-bleeding in our
study was far lower than that of APC. Additionally, EIS treatment help avoiding life-threatening
adverse event caused by APC treatment. EIS treatment is superior to APC in terms of re-bleeding
of SBAs.
#I think it's problematic to compare studies done in different ways. The authors need to pick
up enough evidence to compare them or just mention the possibility only. This answer is not
sufficient.
Minor comments:
1) In table 1, “length of stay” seems to be a result rather than patients characteristics. It may
indicate that treatment intervention with EIS significantly shortened the length of stay.
Reply: Thanks for your comments. We appreciated your suggestion and we have added more
information.
2) I point out a spelling mistake. In “Introduction” of line 7, “small angioectasias (SBAs)” should
be corrected to “small bowel angioectasias (SBAs)”.
Reply: Thanks for your comments. We appreciated your suggestion and we have revised it.
3) “RBC transfusion before admission, multiple lesions (# 3) and EIS treatment were
significantly associated with re-bleeding in patients with SBAs (all P <0.05, Table 4)..” There
is one more period in this sentence.
Reply: Thanks for your comments. We appreciated your suggestion and we have revised it.
SBAs (all P <0.05, Table 4)..” There is one more period in this sentence.
#Well corrected