Reviewer ’s report  
 
Title:  Systematic review with network meta -analysis: dual therapy for high -risk bleeding peptic 
ulcers  
 
Version: 0 Date: 21 Dec 2016 
 
Reviewer:  Stavros  Antoniou  
 
Reviewer’s report:  
 
This is an exceptionally interesting manuscript with sound methodology, well -established 
rationale, and relevant and justified study endpoints.  
 
Below are some essential and some discretionary comments.  
 
1. Page 5, line 37, Search strategy: Please provide the search terms combination for at least one 
database, according to the PRISMA guidelines.  
 
2. Page 6, line 1, Selection criteria: Why were studies comparing dual therapy with types of 
therapy other than epinephrine  monotherapy or other dual therapies excluded? These RCTs could 
share a common comparator, and relevant analyses could further inform the indirect network.  
 
3. Page 7, line 16, Study quality: Was conflict of interest/industry sponsorship documented and 
included in the risk of bias assessment (for example under the component "other bias" in the 
Cochrane Risk of Bias Tool)? This may be a significant source of bias, which needs to be 
accounted for in the analysis.  
 
4. Page 8, line 7, Data Analysis: "Even if the differences in effect size among treatments were 
small, clinical decisions about the choice of treatments could be suggested based on the 
probabilities of treatment ranking." Several network meta -analysis experts would argue against 
this comment.  
 
5. Page 8 , line 33, Results: Please provide a short description of the network geometry according 
to the PRISMA NMA guidelines (http://www.prisma -
statement.org/documents/PRISMA%20NMA%20checklist.pdf) For example, it would be of 
great importance to the reader to kno w for which treatments there was both direct and indirect 
evidence available.  
 
6. Page 9, line line 19, Figure 2: Please define the interrupted connecting lines in the footnote; do 
they stand for indirect comparisons?  
 
7. Page 9, line line 37, Additional fil e 3: Fig. S2: Publication bias may be present with regard to 
mortality (graph C) according to the funnel plot.  
 
8. Page 9, line line 37, Additional file 4: Table S2: Are the listed values in logarithmic scale 
(logOR)? It needs to be reported.  
 
9. Page 9, line line 43, Figure 3: Please define values below and above 1 and whether they 
suggest beneficial or harmful comparative effect for the treatment in the row or in the column.  
 
10. Page 9, line 43, Results from the network meta -analysis: "a trend  toward reduced rebleeding 
rate compared with epinephrine plus thrombin (OR 0.44, 95% Credible interval (CrI) 0.10 -1.84), 
epinephrine plus thermal coagulation (OR 0.62, 95% CrI 0.19 -2.22) and epinephrine plus 
sclerosants (OR 0.29, 95% CrI 0.09 -0.97)" The w ording and the CrIs do not read well. The CrIs 
are too wide to make statements about trend.  
 
11. Page 10, line 15, Results from the network meta -analysis: "With respect to mortality, all 
comparisons among the dual therapies showed no statistical significanc e." Can this be related to 
the scarcity of events?  
 
12. Page 10, line 24, Figure 4: Something is wrong with the figure. According to the rankograms, 
epinephrine as monotherapy has the highest possibility of being the best treatment in terms of re -
bleeding, which does not match with the manuscript. It would be helpful to include a ranking 
table (as a supplementary file) with the absolute values of the possibilities of each treatment 
being the best, second best etc. for the various outcome measures.  
 
13. Page 1 0, line 39, Results from the network meta -analysis: "as this treatment had more 
probability of causing extensive tissue necrosis and perforations" I have the impression that 
relevant data were individually not collected. Is that correct? If yes, then it is  not appropriate to 
make such a statement.  
 
14. Page 10, line 58, Additional file 5: Table S3: What does "medical treatments" include?  
 
15. Page 11, line 4, Discussion: May the year of publication introduce inconsistency across trials, 
which may influence ou tcomes (for example, due to improved endoscopic methods)? This 
consideration needs to be discussed.  
 
16. The Results and the Discussion cannot be assessed, unless comment #9 will be addressed.  
 
17. It would be interesting to see the contribution of each stud y to the whole network. It is 
suggested to provide a contribution plot and a study limitations graph based on these 
contributions, as described in Salanti et al. Evaluating the Quality of Evidence from a Network 
Meta -Analysis. PLOS One 9(7):e99682.  
 
18. Ple ase fill out item 27 on the PRISMA checklist.  
 
Are the methods appropriate and well described?  
If not, please speci fy what is required in your comments to the authors.  
 
Yes 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please specify what asp ects require further 
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation that may in any way gain or lose financially from the publication of this 
manus cript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests.  
I agree to the open peer review policy of the journal. I understand that my name will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any att achments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available under an Open Access Creative Commons 
CC-BY license ( http://creativecomm ons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the editors, which will not be published . 
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title:  Systematic review with network meta -analysis: dual therapy for high -risk bleeding peptic 
ulcers  
 
Version: 0 Date: 21 Dec 2016 
 
Reviewer:  Stavros  Antoniou  
 
Reviewer’s report:  
 
This is an exceptionally interesting manuscript with sound methodology, well -established 
rationale, and relevant and justified study endpoints.  
 
Below are some essential and some discretionary comments.  
 
1. Page 5, line 37, Search strategy: Please provide the search terms combination for at least one 
database, according to the PRISMA guidelines.  
 
2. Page 6, line 1, Selection criteria: Why were studies comparing dual therapy with types of 
therapy other than epinephrine  monotherapy or other dual therapies excluded? These RCTs could 
share a common comparator, and relevant analyses could further inform the indirect network.  
 
3. Page 7, line 16, Study quality: Was conflict of interest/industry sponsorship documented and 
included in the risk of bias assessment (for example under the component "other bias" in the 
Cochrane Risk of Bias Tool)? This may be a significant source of bias, which needs to be 
accounted for in the analysis.  
 
4. Page 8, line 7, Data Analysis: "Even if the differences in effect size among treatments were 
small, clinical decisions about the choice of treatments could be suggested based on the 
probabilities of treatment ranking." Several network meta -analysis experts would argue against 
this comment.  
 
5. Page 8 , line 33, Results: Please provide a short description of the network geometry according 
to the PRISMA NMA guidelines (http://www.prisma -
statement.org/documents/PRISMA%20NMA%20checklist.pdf) For example, it would be of 
great importance to the reader to kno w for which treatments there was both direct and indirect 
evidence available.  
 
6. Page 9, line line 19, Figure 2: Please define the interrupted connecting lines in the footnote; do 
they stand for indirect comparisons?  
 
7. Page 9, line line 37, Additional fil e 3: Fig. S2: Publication bias may be present with regard to 
mortality (graph C) according to the funnel plot.  
 
8. Page 9, line line 37, Additional file 4: Table S2: Are the listed values in logarithmic scale 
(logOR)? It needs to be reported.  
 
9. Page 9, line line 43, Figure 3: Please define values below and above 1 and whether they 
suggest beneficial or harmful comparative effect for the treatment in the row or in the column.  
 
10. Page 9, line 43, Results from the network meta -analysis: "a trend  toward reduced rebleeding 
rate compared with epinephrine plus thrombin (OR 0.44, 95% Credible interval (CrI) 0.10 -1.84), 
epinephrine plus thermal coagulation (OR 0.62, 95% CrI 0.19 -2.22) and epinephrine plus 
sclerosants (OR 0.29, 95% CrI 0.09 -0.97)" The w ording and the CrIs do not read well. The CrIs 
are too wide to make statements about trend.  
 
11. Page 10, line 15, Results from the network meta -analysis: "With respect to mortality, all 
comparisons among the dual therapies showed no statistical significanc e." Can this be related to 
the scarcity of events?  
 
12. Page 10, line 24, Figure 4: Something is wrong with the figure. According to the rankograms, 
epinephrine as monotherapy has the highest possibility of being the best treatment in terms of re -
bleeding, which does not match with the manuscript. It would be helpful to include a ranking 
table (as a supplementary file) with the absolute values of the possibilities of each treatment 
being the best, second best etc. for the various outcome measures.  
 
13. Page 1 0, line 39, Results from the network meta -analysis: "as this treatment had more 
probability of causing extensive tissue necrosis and perforations" I have the impression that 
relevant data were individually not collected. Is that correct? If yes, then it is  not appropriate to 
make such a statement.  
 
14. Page 10, line 58, Additional file 5: Table S3: What does "medical treatments" include?  
 
15. Page 11, line 4, Discussion: May the year of publication introduce inconsistency across trials, 
which may influence ou tcomes (for example, due to improved endoscopic methods)? This 
consideration needs to be discussed.  
 
16. The Results and the Discussion cannot be assessed, unless comment #9 will be addressed.  
 
17. It would be interesting to see the contribution of each stud y to the whole network. It is 
suggested to provide a contribution plot and a study limitations graph based on these 
contributions, as described in Salanti et al. Evaluating the Quality of Evidence from a Network 
Meta -Analysis. PLOS One 9(7):e99682.  
 
18. Ple ase fill out item 27 on the PRISMA checklist.  
 
Are the methods appropriate and well described?  
If not, please speci fy what is required in your comments to the authors.  
 
Yes 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please specify what asp ects require further 
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation that may in any way gain or lose financially from the publication of this 
manus cript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests.  
I agree to the open peer review policy of the journal. I understand that my name will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any att achments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available under an Open Access Creative Commons 
CC-BY license ( http://creativecomm ons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the editors, which will not be published . 
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title:  Systematic review with network meta -analysis: dual therapy for high -risk bleeding peptic 
ulcers  
 
Version: 0 Date: 21 Dec 2016 
 
Reviewer:  Stavros  Antoniou  
 
Reviewer’s report:  
 
This is an exceptionally interesting manuscript with sound methodology, well -established 
rationale, and relevant and justified study endpoints.  
 
Below are some essential and some discretionary comments.  
 
1. Page 5, line 37, Search strategy: Please provide the search terms combination for at least one 
database, according to the PRISMA guidelines.  
 
2. Page 6, line 1, Selection criteria: Why were studies comparing dual therapy with types of 
therapy other than epinephrine  monotherapy or other dual therapies excluded? These RCTs could 
share a common comparator, and relevant analyses could further inform the indirect network.  
 
3. Page 7, line 16, Study quality: Was conflict of interest/industry sponsorship documented and 
included in the risk of bias assessment (for example under the component "other bias" in the 
Cochrane Risk of Bias Tool)? This may be a significant source of bias, which needs to be 
accounted for in the analysis.  
 
4. Page 8, line 7, Data Analysis: "Even if the differences in effect size among treatments were 
small, clinical decisions about the choice of treatments could be suggested based on the 
probabilities of treatment ranking." Several network meta -analysis experts would argue against 
this comment.  
 
5. Page 8 , line 33, Results: Please provide a short description of the network geometry according 
to the PRISMA NMA guidelines (http://www.prisma -
statement.org/documents/PRISMA%20NMA%20checklist.pdf) For example, it would be of 
great importance to the reader to kno w for which treatments there was both direct and indirect 
evidence available.  
 
6. Page 9, line line 19, Figure 2: Please define the interrupted connecting lines in the footnote; do 
they stand for indirect comparisons?  
 
7. Page 9, line line 37, Additional fil e 3: Fig. S2: Publication bias may be present with regard to 
mortality (graph C) according to the funnel plot.  
 
8. Page 9, line line 37, Additional file 4: Table S2: Are the listed values in logarithmic scale 
(logOR)? It needs to be reported.  
 
9. Page 9, line line 43, Figure 3: Please define values below and above 1 and whether they 
suggest beneficial or harmful comparative effect for the treatment in the row or in the column.  
 
10. Page 9, line 43, Results from the network meta -analysis: "a trend  toward reduced rebleeding 
rate compared with epinephrine plus thrombin (OR 0.44, 95% Credible interval (CrI) 0.10 -1.84), 
epinephrine plus thermal coagulation (OR 0.62, 95% CrI 0.19 -2.22) and epinephrine plus 
sclerosants (OR 0.29, 95% CrI 0.09 -0.97)" The w ording and the CrIs do not read well. The CrIs 
are too wide to make statements about trend.  
 
11. Page 10, line 15, Results from the network meta -analysis: "With respect to mortality, all 
comparisons among the dual therapies showed no statistical significanc e." Can this be related to 
the scarcity of events?  
 
12. Page 10, line 24, Figure 4: Something is wrong with the figure. According to the rankograms, 
epinephrine as monotherapy has the highest possibility of being the best treatment in terms of re -
bleeding, which does not match with the manuscript. It would be helpful to include a ranking 
table (as a supplementary file) with the absolute values of the possibilities of each treatment 
being the best, second best etc. for the various outcome measures.  
 
13. Page 1 0, line 39, Results from the network meta -analysis: "as this treatment had more 
probability of causing extensive tissue necrosis and perforations" I have the impression that 
relevant data were individually not collected. Is that correct? If yes, then it is  not appropriate to 
make such a statement.  
 
14. Page 10, line 58, Additional file 5: Table S3: What does "medical treatments" include?  
 
15. Page 11, line 4, Discussion: May the year of publication introduce inconsistency across trials, 
which may influence ou tcomes (for example, due to improved endoscopic methods)? This 
consideration needs to be discussed.  
 
16. The Results and the Discussion cannot be assessed, unless comment #9 will be addressed.  
 
17. It would be interesting to see the contribution of each stud y to the whole network. It is 
suggested to provide a contribution plot and a study limitations graph based on these 
contributions, as described in Salanti et al. Evaluating the Quality of Evidence from a Network 
Meta -Analysis. PLOS One 9(7):e99682.  
 
18. Ple ase fill out item 27 on the PRISMA checklist.  
 
Are the methods appropriate and well described?  
If not, please speci fy what is required in your comments to the authors.  
 
Yes 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please specify what asp ects require further 
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation that may in any way gain or lose financially from the publication of this 
manus cript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests.  
I agree to the open peer review policy of the journal. I understand that my name will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any att achments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available under an Open Access Creative Commons 
CC-BY license ( http://creativecomm ons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the editors, which will not be published . 
 
I agree to the open peer review policy of the journal  
assistant