Download Authors* response to Decision Letter

Authors’ response to Decision Letter
"Recent advances on the management of patients with non variceal upper gastrointestinal bleeding"
Dear Editor,
We are grateful for the positive and constructive comments that originated for the review process. We
have responded to the points raised by the reviewers and the editorial comments as follows. We are
submitting a two version of the revised manuscript; a version with the changes highlighted, and a clean
version with all changes accepted.
Reviewer A:
This is an excellent and comprehensive review on the management of patients with non variceal upper
gastrointestinal bleeding. The authors analyse all aspects of non variceal AUGIB and give answers /
recommendations to many clinical questions that emerge in the management of patients with non
variceal bleeding.
Response: We thank the reviewer for the kind comments.
Comments : 1. In the recent published RCT by Villanueva et al. lower mortality was observed only in
patients with variceal bleeding. Patients with peptic ulcer bleeding were not benefited from the
restricted policy and as the authors state the decision to transfuse should be individualized. There is no
evidence that a so restricted transfusion policy (Hb < 70g/L) has any benefit to the patients with peptic
ulcer bleeding.
Response: We agree with the reviewer. We believe that this was a “negative” study, especially regarding
peptic ulcer bleeding. For clarity, we revised the relevant section which now reads:
“However, a more recent RCT on this topic was published by Villanueva et al who randomized 921 patients
(bleeding peptic ulcer 48%, variceal bleeding 24%) with upper GI bleeding to either a restrictive (transfuse at a
hemoglobin level of 70g/L) or liberal (transfuse at a hemoglobin level of 90g/L) transfusion strategy. The patients
were treated according to current standards of care with regards to PPI treatment and endoscopic hemostasis.
Patients treated with the restrictive strategy had significantly lower mortality at 45 days (hazard ratio (HR) = 0.55;
95% confidence interval (CI) 0.33 to 0.92), less re-bleeding, and experienced fewer overall adverse events. These
findings attracted high publicity, but should be interpreted with caution because of high risk of performance bias
(due to lack of blinding) and limited generalizeability (a large proportion of potentially eligible patients was either
not screened or excluded for reasons such as “massive” bleeding or severe comorbidity). Furthermore, the subgroup
analyses on peptic ulcer bleeding versus variceal bleeding, albeit important, were underpowered; therefore no
conclusion could be drawn specifically for patients with peptic ulcer bleeding.
Considerations: All patients should be assessed for evidence of hemodynamic compromise and low hemoglobin
levels. The decision to transfuse should take into account the hemoglobin level, but practitioners should keep in
mind that transfusion may carry risks of complications. This decision should be weighed carefully for each individual
patient. As common sense dictates, hypovolemic patients with acute massive blood loss who may only show a
spuriously small drop in hemoglobin on presentation should be managed proactively according to the hemoglobin
levels that are anticipated to show following volume resuscitation. Similarly, a higher target level of hemoglobin
should be pursued in patients who have low tolerance to anemia because of comorbidities such as coronary artery
disease, cardiac or renal failure. More research is necessary before sound recommendations can be made about the
hemoglobin threshold for transfusion and the target hemoglobin levels. ”
2.
page 13, line 20 : “….should receive IV infusion of high – dose PPI…..” As the authors analyse there
is no evidence from meta analyses and other recent multicenter studies (Andriulli A et al. Am J
Gastroenterol. 2008 and others) that high dose is superior to low dose ppi. I think that the
conclusion/suggestion is rather absolute and is not based on recent evidence.
Response: We acknowledge that this is the most controversial topic of this review but we respectfully
disagree that our suggestion is “rather absolute and not based on recent evidence”. There is no
evidence that high dose is superior to low dose PPI, but at the same time there is no evidence that they
are equivalent. At the same time, there is very strong evidence on the efficacy of high dose PPI, in
contrast to the lower quality of evidence on the efficacy of low dose PPI in western populations. We
have devoted a large proportion of our review to describe the evidence and the controversial guidelines
that exist nowadays. In the end we chose to concur with the international consensus group guidelines.
As we mention in the manuscript: “It seems that, for the time being, a reasonable approach is the approach
chosen by the international consensus group who stated that “strong evidence demonstrates the efficacy of highdose IV PPI therapy after successful endoscopy, but it is not possible to make conclusions regarding the efficacy of
either lower intravenous doses or high-dose oral therapy””
3.
page 15, line 7: PPIs should use should be administered …..
Response: We thank the reviewer for pointing this out. We have corrected it to “PPIs should be
administered...”
-----------------------------------------------------Reviewer B:
This is an excellent review.
Response: We thank the reviewer for the kind comment.
However I believe that the present review needs to report :
1. About the impact of selective serotonin reuptake inhibitors (SSRI) on upper gastrointestinal (GI) nonvariceal bleeding. Recently relative studies addressing this topic have been published. Some studies
found a strong significant association between SSRIs and upper GI non-variceal bleeding and the
association of SSRIs and NSAIDs or corticosteroids with upper GI non-variceal bleeding. Therefore, given
the widespread use of SSRIs, antiplatelet drugs and NSAIDs, we conside that gastroenterologists should
turn their attention to bleeding as adverse effect and interaction respectively.
Response: We agree that the issue of SSRIs and other medications that may increase the risk of (upper)
GI bleeding, such as non-aspirin antiplatelets, anticoagulants (including the new oral ones), and
corticosteroids is an important one. We are currently conducting a rigorous network meta-analysis in an
attempt to quantify the effect of those (and other risk factors) and the interaction among them. We
have been negatively surprised with the low quality of the evidence available (mainly due to the
difficulty to adequately adjust for confounding factors). Therefore, until we finish working on this
network meta-analysis we would rather refrain from any discussions or suggestions on measures for
secondary prophylaxis of NVUGI bleeding relating to medications other than NSAIDs and low-dose ASA.
The consensus guidelines have also chosen not to comment on this issue, but hopefully they will address
this when they are updated.
2. A more clear comment about the transfusion policy. Nowadays, the group of elder patients with
upper GI non-variceal bleeding and comorbid diseases such as coronary artery disease, cardiac or
chronic renal failure becomes larger. In this review, hemoglobin of 7.0 g/dl is reported as the limit for
transfusion. However, it should be emphasized that there are exceptions, as patients belonging to the
above mentioned group are in high risk of serious events in case of such a decrease of hemoglobin. As a
result, a report about exceptions for the hemoglobin level for transfusion would be useful.
Response: We agree with the reviewer. In respond to this comment and to a comment raised by the
other reviewer, we have revised the text as follows.
“Considerations: All patients should be assessed for evidence of hemodynamic compromise and low hemoglobin
levels. The decision to transfuse should take into account the hemoglobin level, but practitioners should keep in
mind that transfusion may carry risks of complications. This decision should be weighed carefully for each individual
patient. As common sense dictates, hypovolemic patients with acute massive blood loss who may only show a
spuriously small drop in hemoglobin on presentation should be managed proactively according to the hemoglobin
levels that are anticipated to show following volume resuscitation. Similarly, a higher target level of hemoglobin
should be pursued in patients who have low tolerance to anemia because of comorbidities such as coronary artery
disease, cardiac or renal failure. More research is necessary before sound recommendations can be made about the
hemoglobin threshold for transfusion and the target hemoglobin levels. ”
--------------------------------------------------------Editor's comments:
The first 3 authors (if more than 6) of ref 7 should be provided
Response: We thank the Editor for pointing this out. We have corrected this.