PEER REVIEW HISTORY. (This paper received three reviews from its previous journal but only two reviewers agreed to published their review.

Transcription

1 PEER REVIEW HISTORY BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form ( and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below. This paper was submitted to a another journal from BMJ but declined for publication following peer review. The authors addressed the reviewers comments and submitted the revised paper to BMJ Open. The paper was subsequently accepted for publication at BMJ Open. (This paper received three reviews from its previous journal but only two reviewers agreed to published their review.) TITLE (PROVISIONAL) AUTHORS ARTICLE DETAILS Morphine in acute coronary syndrome: systematic review and meta-analysis Duarte, Gonçalo Silva; Nunes-Ferreira, Afonso; Brogueira Rodrigues, Filipe; Pinto, Fausto; Ferreira, Joaquim J; Costa, Joao; Caldeira, Daniel VERSION 1 REVIEW Aakash Garg Newark Beth Israel Medical Center, Newark, NJ USA 15-Aug-2018 Role of morphine in ACS patients is an important topic for both cardiologists and ER physicians. Overall, the authors should be commended for the comprehensiveness of their analysis. However one of the major limitations of the studies is non-inclusion of several recent studies evaluating role of opioids (morphine and fentanyl) in patients on newer P2Y12 inhibitors (for example, Farag M et al, Morphine Analgesia Pre-PPCI Is Associated with Prothrombotic State, Reduced Spontaneous Reperfusion, and Greater Infarct Size. Thromb Haemost 2018) I have following comments: 1) Abstract: Objective section- 3rd line- Please rephrase. Could use- "However, controversy exists regarding its routine use due to potential safety concerns" Eligibility criteria: Instead of longitudinal studies, specificy RCTs and observational studies 2) Introduction: Rephrase and shorten first paragraph: "Cardiovascular events are the leading...share of this is due to acute coronary syndromes (ACS)". Please rephrase this: "We performed a systematic review of randomized controlled...hypothesizing that we would find a clinically meaningful result" You haven't defined CV risk yet with morphine, so it might be better to use "evaluate safety of morphine in ACS"

2 3) Methods: Inclusion and exclusion criteria need to be clearly defined. Please describe principle and utility of VerifyNow assay in 1-2 lines. 4) Results: If available, one important variable to look at would be percentage use and type of P2Y12 inhibitors in these studies. Specifically, newer more potent P2Y12 inhibitors could potentially have different effect profile with morphine compared to clopidogrel. MACE: Please rephrase "Morphine was associated with a nonsignificant 20% increase in the risk of MACE" to "morphine was associated with a non significant trend towards increased risk of MACE" Please clarify the word "overlapping" in this sentence "We additionally pooled results using the three trials that reported results using the MEA method, which resulted in overlapping results at one hour..." 5) Discussion: Overall, discussion section needs major editing. Please describe your findings briefly in first paragraph of discussion section. Then, it would be helpful to describe briefly findings of the 2-3 major included studies which would give a broader idea to readers about the topic. It would also be prudent to comment upon literature on effect of other opioids (eg fentanyl) on platelet reactivity. Authors have explained the limitations in detail. However, one of the major outcomes affected by increased platelet reactivity could be acute ST which is missing. Hence, without this, conclusions regarding association of increased platelet reactivity due to morphine use and signal of increased mortality cannot be ascertained. Rita Pavasini UO Cardiologia, Azienda Ospedaliero Universitaria S.Anna Ferrara 30-Aug-2018 This is a meta-analysis about the effect of morphine in acute coronary syndromes in terms of MACE, in-hospital mortality and platelet reactivity. Authors found a great amount of publication bias and after sensitivity analysis in-hospital mortality and also MACE are not significantly increased in patients treated with morphine. Analyses are sometimes difficult to be understood ( e.g: sub-group analysis about the study design where the comparator are completely different), and at the same time some data are missing to understand the real conclusion of this paper (dosage of morphine, route of administration of morphine, dual antiplatelet therapy, time of administration of morphine). - Extensive revision of English grammar is necessary - There is a bit of confusion in the definition of the study type: this is a systematic review, but also aa meta-analysis because there is an application of statistics on aggregate and already published data. For this reason, the PRISMA guidelines has to be followed for the conduction of the meta-analysis and also in the

3 interpretation of the data, also because the PRISMA checklist is enclosed to the file. So I suggest to better underline the use of PRISMA guidelines in methods also in the abstract, and to check for the definition of the study type through the paper e.g: in strength and limitation the paper is defined only a systematic review) - Line introduction: reference is missing. - How were analyzed references in languages different from English? - Why not to change table 1 of the supplemental online material in a figure, similar to those of the publication bias for RCT in line with the Cochrane method? IT would be easier to be understood. - I would move the analysis on bias as last paragraph, and change the title in quality assessment. - Please perform a subgroup analysis RCT vs observational study for the main outcomes. - Sub analysis about study design : please better specify the kind of sub-analysis is that for RCT vs observational? - Which is the definition used for cardiogenic shock and heart failure? On how many patients? - After sensitivity analysis for both in-hospital mortality and MACE how many patients have been included? - Considering that after the exclusion of studies with high bias risk the analysis were negative for in-hospital mortality and MACE, the conclusion of the paper are not adequately drawn and data are inconclusive, please better explain this in the discussion, but also change the conclusion in both abstract and the main paper. - A big limitation of this study is related to the fact that it is not analyzed the way of administration of morphine as well as the kind of dual antiplatelet therapy used. Is it possible to perform metaregression for example on the type of P2Y12 inhibitor used, was it administered crushed or integer? - How to compare study where the comparator is completely different ( e.g: metoprolol and indoprofen)? Robert West University of Leeds 24-Oct-2018 Overall this is a nice piece of work, well reported, and addressing a good clinical question. PRISMA followed well. One of the major strengths of this manuscript is that the authors are able to combine results from RCTs with results from observational studies. It is noted that often observational studies have far larger N than RCTs and this is the case here, with concerns, which are stated, about overconfidence in precision. The authors present a solution: a precision correction of 0.1. This needs considerably more detail including the justification for the 0.1 value. There is an issue about variable exposure to morphine, with considerable differences in dose and means of administration. This might be emphasized more in the limitations section of the conclusion. Looking at the References, the first is Organization WH. Should this be World Health Organization? Further references for the precision correction would be welcome if possible.

4 Irene SL Zeng istatdome (registered) online datalab, New Zealand and Mental Health and Addiction service, Middlemore hospital, Counties Manukau Health, New Zealand 29-Oct-2018 Congratulation for all authors having completed such a significant work. My comments and suggestions are listed as followed: 1) Data collection process: The main concern for the data extraction from these 11 studies is that, it has not included any information of the antiplatelet agent (for example, How were the antiplatelet agent administered to patients and what were the majority type of the antiplatelet agent prescribed in each study?). 2) Method: All studies did not include any information relating to administration of antiplate agent which is a critical confounder. An example is that, IMPRESSION trial (Kubica J, Adamski P, Ostrowska M, et al ) demonstrated that when dose of ticagrelor at 180 mg, the interaction with morphine can be overcome and the antiplatelet effect can be maintained. Due to the controversial results presenting, it would be better to have sensitivity analysis showing results in all outcomes for: a) with and without study with critical bias; b) with and without study with predominant weight (such as Maine's study in the mortality and MACE) Using the precision correction of 0.1 to pool study with critical bias is not convincing. 3) Results: a) All I square reported as 0%, are they being zero to 4 decimal place %? If there is a non-zero significant figure, then please report it. b) In table 2, please include any information relating to administration of antiplatelet agent. c) In table 2, please provide the mortality rate and MACE rate for each study. d) Result for hospital mortality: p9 line 16-19: Subgroup analysis... This result is not clear. Dose authors try to state that, the subgroup analysis for different study design and ACS subtype all have nonsignificant results in terms of comparing Morphine group verse the control group? If so,it will be better to state these results clearly. Similar comments are for the MACE, Haemorrhage and platelet reactivity results interpretation. e) please provide subgroup analysis results in the result section separately for each outcome.

5 Reviewer: 1 Reviewer Name: Aakash Garg VERSION 1 AUTHOR RESPONSE Institution and Country: Newark Beth Israel Medical Center, Newark, NJ, USA Please state any competing interests or state None declared : None declared Role of morphine in ACS patients is an important topic for both cardiologists and ER physicians. Overall, the authors should be commended for the comprehensiveness of their analysis. However, one of the major limitations of the studies is non-inclusion of several recent studies evaluating role of opioids (morphine and fentanyl) in patients on newer P2Y12 inhibitors (for example, Farag M et al, Morphine Analgesia Pre-PPCI Is Associated with Prothrombotic State, Reduced Spontaneous Reperfusion, and Greater Infarct Size. Thromb Haemost 2018) I have following comments: 1) Abstract: Objective section- 3rd line- Please rephrase. Could use- "However, controversy exists regarding its routine use due to potential safety concerns" Eligibility criteria: Instead of longitudinal studies, specify RCTs and observational studies Authors reply: We thank the reviewer for their comment. We have amended these sections in line with the recommendations. 2) Introduction: Rephrase and shorten first paragraph: "Cardiovascular events are the leading...share of this is due to acute coronary syndromes (ACS)". Authors reply: We thank the reviewer for their comment. We have amended these sections in line with the recommendations. This section now reads Worldwide, cardiovascular events are the leading cause of death. 1 The burden of disease will likely remain high as the incidence of cardiovascular events is expected to continue increasing. Please rephrase this: "We performed a systematic review of randomized controlled...hypothesizing that we would find a clinically meaningful result". You haven't defined CV risk yet with morphine, so it might be better to use "evaluate safety of morphine in ACS" Authors reply: We thank the reviewer for their comment. We have amended the section, and followed the suggestion. The section now reads: We conducted a systematic review of randomized-controlled trials (RCTs) and observational studies to evaluate the safety of morphine use in ACS, hypothesizing that we would find a clinically meaningful result. 3) Methods: Inclusion and exclusion criteria need to be clearly defined. Please describe principle and utility of VerifyNow assay in 1-2 lines.

6 Authors reply: We thank the reviewer for the criticism. We rephrased the eligibility criteria in order to make this subsection clear for readers. We also explained briefly the basic principles of the VerifyNow assay in the Methods section. 4) Results: If available, one important variable to look at would be percentage use and type of P2Y12 inhibitors in these studies. Specifically, newer more potent P2Y12 inhibitors could potentially have different effect profile with morphine compared to clopidogrel. Authors reply: We thank the reviewer for their comment. Although this is an interesting point, as the P2Y12 inhibitors will be the same within individual studies, and will not invalidate study results. We anticipate that this increases the heterogeneity between different studies and have referred to this in the discussion section. MACE: Please rephrase "Morphine was associated with a non-significant 20% increase in the risk of MACE" to "morphine was associated with a non-significant trend towards increased risk of MACE" Authors reply: We thank the reviewer for their comment. We have incorporated the suggested phrase. Please clarify the word "overlapping" in this sentence "We additionally pooled results using the three trials that reported results using the MEA method, which resulted in overlapping results at one hour..." Authors reply: We thank the reviewer for their comment. We have amended the sentence, which now reads: We additionally pooled results using the three trials that reported results using the MEA method. These results were consistent with those using the VerifyNow method at both one hour and two hours after morphine administration. 5) Discussion: Overall, discussion section needs major editing. Please describe your findings briefly in first paragraph of discussion section. Then, it would be helpful to describe briefly findings of the 2-3 major included studies which would give a broader idea to readers about the topic. It would also be prudent to comment upon literature on effect of other opioids (eg fentanyl) on platelet reactivity. Authors have explained the limitations in detail. However, one of the major outcomes affected by increased platelet reactivity could be acute ST which is missing. Hence, without this, conclusions regarding association of increased platelet reactivity due to morphine use and signal of increased mortality cannot be ascertained. Authors reply: We thank the reviewer for their comments. We have added a small paragraph summarizing the findings as suggested. We further referred to recent evidence on the effect of fentanyl in ACS. We have extracted data regarding the frequency of stent thrombosis, which was non-significant, and can be found in the supplementary material.

7 Reviewer: 2 Reviewer Name: Rita Pavasini Institution and Country: UO Cardiologia, Azienda Ospedaliero Universitaria S.Anna Ferrara Please state any competing interests or state None declared : None declared This is a meta-analysis about the effect of morphine in acute coronary syndromes in terms of MACE, in-hospital mortality and platelet reactivity. Authors found a great amount of publication bias and after sensitivity analysis in-hospital mortality and also MACE are not significantly increased in patients treated with morphine. Analyses are sometimes difficult to be understood ( e.g: sub-group analysis about the study design where the comparator are completely different), and at the same time some data are missing to understand the real conclusion of this paper (dosage of morphine, route of administration of morphine, dual antiplatelet therapy, time of administration of morphine). - Extensive revision of English grammar is necessary Authors reply: We thank the reviewer for their comment. We have reviewed the English grammar throughout the manuscript. - There is a bit of confusion in the definition of the study type: this is a systematic review, but also aa meta-analysis because there is an application of statistics on aggregate and already published data. For this reason, the PRISMA guidelines has to be followed for the conduction of the meta-analysis and also in the interpretation of the data, also because the PRISMA checklist is enclosed to the file. So I suggest to better underline the use of PRISMA guidelines in methods also in the abstract, and to check for the definition of the study type through the paper e.g: in strength and limitation the paper is defined only a systematic review) Authors reply: We thank the reviewer for their comment. We have added the following line to the abstract: We followed the MOOSE and PRISMA guidelines. - Line introduction: reference is missing. Authors reply: We thank the reviewer for their comment. We do not have over 30 lines in the introduction, and therefore do not understand what the reviewer is referencing. - How were analyzed references in languages different from English? Authors reply: We thank the reviewer for their comment. In this review we had no need for translation, and so have not added the text that reports how we would have conducted this. However, this is available in the publicly available review protocol on PROSPERO. - Why not to change table 1 of the supplemental online material in a figure, similar to those of the publication bias for RCT in line with the Cochrane method? IT would be easier to be understood. Authors reply: We thank the reviewer for their comment. In the case of this table we have used the Cochrane risk of bias tool for RCTs, but also a newer and not well-known tool, ROBINS. As there is no

8 established form of presenting results for ROBINS, we judged that a table would transmit the more information for most potential readers of the review. - I would move the analysis on bias as last paragraph, and change the title in quality assessment. Authors reply: We thank the reviewer for their comment. As this was conducted before the metaanalysis, and the bias-weighted correction is an essential part of the analysis, we believe that it may be best to maintain the current organization, in line with most systematic reviews. - Please perform a subgroup analysis RCT vs observational study for the main outcomes. Authors reply: We thank the reviewer for their comment. We conducted this review, which can be found in the last lines of every paragraph reporting every key outcome. - Sub analysis about study design : please better specify the kind of sub-analysis is that for RCT vs observational? Authors reply: We thank the reviewer for their comment. We have added the following amendment: Pre-planned subgroup analyses considering study design (RCTs and observational studies). - Which is the definition used for cardiogenic shock and heart failure? On how many patients? Authors reply: We thank the reviewer for their comment. For all outcomes we pooled results using the definitions used in each individual study. We have added the number of participants analysed for each outcome. - After sensitivity analysis for both in-hospital mortality and MACE how many patients have been included? Authors reply: We thank the reviewer for their comment. We have added the number of participants analysed for each outcome. - Considering that after the exclusion of studies with high bias risk the analysis were negative for in-hospital mortality and MACE, the conclusion of the paper are not adequately drawn and data are inconclusive, please better explain this in the discussion, but also change the conclusion in both abstract and the main paper. Authors reply: We thank the reviewer for their comment. By removing the observational studies there is a further problem, and likely a more important one, arises, namely that the results become severely underpowered, with under 600 participants for both outcomes. This being so, and as can be seen by the extremely wide confidence intervals of the sensitivity analyses, we do not consider that these results are as reliable as the main results. Although this is an important point for discussion, we believe in does not invalidate the overall study conclusions. - A big limitation of this study is related to the fact that it is not analyzed the way of administration of morphine as well as the kind of dual antiplatelet therapy used. Is it possible to perform meta-regression for example on the type of P2Y12 inhibitor used, was it administered crushed or integer?

9 Authors reply: We thank the reviewer for their comment. We have now reviewed and described the antiplatelet agents used in Table 1. - How to compare study where the comparator is completely different (e.g. metoprolol and indoprofen)? Authors reply: We thank the reviewer for their comment. In such cases, as the comparators are the same within each individual study, different comparators contribute heterogeneity, though do not alter the comparative efficacy results. Reviewer: 3 Reviewer Name: Robert West Institution and Country: University of Leeds Please state any competing interests or state None declared : None declared. Overall this is a nice piece of work, well reported, and addressing a good clinical question. PRISMA followed well. One of the major strengths of this manuscript is that the authors are able to combine results from RCTs with results from observational studies. It is noted that often observational studies have far larger N than RCTs and this is the case here, with concerns, which are stated, about overconfidence in precision. The authors present a solution: a precision correction of 0.1. This needs considerably more detail including the justification for the 0.1 value. There is an issue about variable exposure to morphine, with considerable differences in dose and means of administration. This might be emphasized more in the limitations section of the conclusion. Authors reply: We thank the reviewer for their comment. Regarding the precision correction, in our opinion, the estimates of an observational studies do not have the same weight as data from RCTs. Therefore, this approach aims to decrease the risk of bias of the final estimates and it is also a conservative approach. In order to make this clear for reviewers and readers we added a statement to the discussion as a possible limitation. We also added a sentence about the issue of dose and route of administration of morphine. Looking at the References, the first is Organization WH. Should this be World Health Organization? Further references for the precision correction would be welcome if possible. Authors reply: We thank the reviewer for their comment. We have amended the reference as suggested. Reviewer: 4 Reviewer Name: Irene SL Zeng Institution and Country: istatdome (registered) online datalab, New Zealand and Mental Health and Addiction service, Middlemore hospital, Counties Manukau Health, New Zealand

10 Please state any competing interests or state None declared : None declared Congratulation for all authors having completed such a significant work. My comments and suggestions are listed as followed: 1) Data collection process: The main concern for the data extraction from these 11 studies is that, it has not included any information of the antiplatelet agent (for example, how were the antiplatelet agent administered to patients and what were the majority type of the antiplatelet agent prescribed in each study?). 2) Method: All studies did not include any information relating to administration of antiplatelet agent which is a critical confounder. An example is that, IMPRESSION trial (Kubica J, Adamski P, Ostrowska M, et al. 2016) demonstrated that when dose of ticagrelor at 180 mg, the interaction with morphine can be overcome and the antiplatelet effect can be maintained. Due to the controversial results presenting, it would be better to have sensitivity analysis showing results in all outcomes for: a) with and without study with critical bias; b) with and without study with predominant weight (such as Maine's study in the mortality and MACE) Using the precision correction of 0.1 to pool study with critical bias is not convincing. Authors reply: As answered previously in our opinion, the estimates of an observational studies do not have the same weight as data from RCTs. Therefore, by applying the precision correction we aimed to decrease the risk of bias of the final estimates in a conservative approach. In order to make this clear for reviewers and readers we added a statement to the discussion as a possible limitation 3) Results: a) All I square reported as 0%, are they being zero to 4 decimal place %? If there is a nonzero significant figure, then please report it. Authors reply: We were only able to retrieve these data without further decimals. However, we do not think that adding more decimals would increase the information about the estimates and their reliability. b) In table 2, please include any information relating to administration of antiplatelet agent. Authors reply: We thank the reviewer for their comment. We have now reviewed and described the antiplatelet agents used in Table 1. c) In table 2, please provide the mortality rate and MACE rate for each study. Authors reply: We thank the reviewer for their comment. We have now reviewed and described the antiplatelet agents used in Table 1. d) Result for hospital mortality: p9 line 16-19: Subgroup analysis...

11 This result is not clear. Dose authors try to state that, the subgroup analysis for different study design and ACS subtype all have non-significant results in terms of comparing Morphine group verse the control group? If so, it will be better to state these results clearly. Similar comments are for the MACE, Haemorrhage and platelet reactivity results interpretation. e) please provide subgroup analysis results in the result section separately for each outcome. Authors reply: We thank the reviewer for their comment. The p-values refer to the interaction test between the subgroups described. Making explicit considerations using only the results for the individual subgroups would likely not be a correct statistical practice, though we would be willing to do this should the Editors deem it necessary. VERSION 2 REVIEW Aakash Garg Newark Beth Israel Medical Center, NJ, USA 08-Dec-2018 Thank you for making the suggested changes. Rita Pavasini UO Cardiologia, Azienda Ospedaliero Universitaria di Ferrara, Ferrara, Italy 09-Dec-2018 Authors replied to questions, however I still have some major concerns: 1: INTRODUCTION: However, the activation of opioid receptors in the myenteric plexus decreases gut motility and secretion, inhibiting the activation of P2Y12 inhibitors by decreasing their absorption and bioavailability. The reference is missing. 2: I think it is a bit ambitious to consider these data more than hypothesis generating. Considering that after the exclusion of studies with high bias risk the analysis were negative for inhospital mortality and MACE. As authors state By removing the observational studies there is a further problem, and likely a more important one, arises, namely that the results become severely underpowered, with under 600 participants for both outcomes. But this is not a justification to consider that Morphine was associated with an increased risk of in-hospital mortality and MACE but the high risk of bias leads to low result confidence as stated in the conclusion of the abstract. 3: it is not useful to perform sub-group analysis independently of the heterogeneity of the results. This is a non-sense. Heterogeneity is a part of the analysis and results have to be interpreted in light of heterogeneity. 4: A table with definition of shock and heart failure for each study have to be added. Robert M West University of Leeds 14-Dec-2018 The remaining issue is the choice of w=0.1 for the weighting of observational studies. It does appear to be a reasonable value

12 having read the cited publications. Nonetheless the author's need to justify their choice Irene SL Zeng istatdome online datalab and Mental health and Addiction service, Counties Manukau Health 16-Dec-2018 The main paper and supplementary are very informative. The reporting results for the following outcomes need to correct though for its I square values, and please include the p values for the heterogeneity tests. They are not consistent with the supplementary results. 1) The I square for hypotension is 5% and p value is ) The I square for heart failure is 33% and p value is ) The I square for nauseaa/emesis is 44% and p value is ) The I square for 1-hour post morphine administration is 24%, using MAE method and p value is ) The I square for 2-hour post morphine administration is 82%, using MAE method and p value is Please comment on the significant heterogeneity of 2-hour post morphine administration, using MAE method across studies, and include the hospital mortality and MCE rate in table 1 and 2 where available. The paper has great improvement in its result presentation with the anti-platelet information included in the tables. VERSION 2 AUTHOR RESPONSE Reviewer: 1 Reviewer Name: Aakash Garg Institution and Country: Newark Beth Israel Medical Center, NJ, USA Please state any competing interests or state None declared : None Thank you for making the suggested changes. Author s reply: Thank you. Reviewer: 2 Reviewer Name: Rita Pavasini Institution and Country: UO Cardiologia, <br>azienda Ospedaliero Universitaria di Ferrara,<br>Ferrara,<br>Italy Please state any competing interests or state None declared : None declared Authors replied to questions, however I still have some major concerns: 1: INTRODUCTION: However, the activation of opioid receptors in the myenteric plexus decreases gut motility and secretion, inhibiting the activation of P2Y12 inhibitors by decreasing their absorption and bioavailability. The reference is missing. Author s reply: Thank you. We have added a reference, as suggested. 2: I think it is a bit ambitious to consider these data more than hypothesis generating.

13 Considering that after the exclusion of studies with high bias risk the analysis were negative for in-hospital mortality and MACE. As authors state By removing the observational studies there is a further problem, and likely a more important one, arises, namely that the results become severely underpowered, with under 600 participants for both outcomes. But this is not a justification to consider that Morphine was associated with an increased risk of inhospital mortality and MACE but the high risk of bias leads to low result confidence as stated in the conclusion of the abstract. Author s reply: Thank you. We agree that the results are mostly hypothesis-generating due to the low quality of evidence and we further stressed this point in the discussion. The low confidence was a result of a weighting of the multiple considerations in the GRADE assessment. As for the analysis of the results according to study design/risk of bias, we should consider the following points: 1) the isolated value of the estimate was non-significant; 2) but the p-value for interaction (of the estimates according to study design/risk of bias) was non-significant thus we may consider that study design/risk of bias does not have impact in the analyses; 3) In subgroup analyses, the confidence intervals are expected to increase, but the point estimates are at least very similar. Therefore, we chose to consider that the low confidence results from the global analysis of GRADE where the high risk of bias determined by the study design per se is crucial. 3: it is not useful to perform sub-group analysis independently of the heterogeneity of the results. This is a non-sense. Heterogeneity is a part of the analysis and results have to be interpreted in light of heterogeneity. Author s reply: Thank you for this criticism. These analyses were pre-specified in the review and we wanted to stress that this was predefined as often subgroup analyses are suggested to study the potential source of statistical heterogeneity. In order to make the methodology clearer we erased this segment of the sentence independently of the heterogeneity of the results 4: A table with definition of shock and heart failure for each study have to be added. Author s reply: Thank you. We used the definitions used in the individual trials. We have added the following statement the Methods section. Secondary outcomes comprised: additional safety outcomes, as defined within the included studies. Reviewer: 3 Reviewer Name: Robert M West Institution and Country: University of Leeds Please state any competing interests or state None declared : None declared The remaining issue is the choice of w=0.1 for the weighting of observational studies. It does appear to be a reasonable value having read the cited publications. Nonetheless the author's need to justify their choice Author s reply: Thank you. We have added the following sentence in the Methods section justifying this choice: This conservative weight factor was based on expert-based clinical grounds. Reviewer: 4 Reviewer Name: Irene SL Zeng Institution and Country: istatdome online datalab and Mental health and Addiction service, Counties Manukau Health Please state any competing interests or state None declared : None declared

14 The main paper and supplementary are very informative. The reporting results for the following outcomes need to correct though for its I square values, and please include the p values for the heterogeneity tests. They are not consistent with the supplementary results. 1) The I square for hypotension is 5% and p value is 0.81 Author s reply: Thank you. This has been corrected. 2) The I square for heart failure is 33% and p value is 0.20 Author s reply: Thank you. This has been corrected. 3) The I square for nausea/emesis is 44% and p value is 0.15 Author s reply: Thank you. This has been corrected. 4) The I square for 1-hour post morphine administration is 24%, using MAE method and p value is 0.25 Author s reply: Thank you. This has been corrected. 5) The I square for 2-hour post morphine administration is 82%, using MAE method and p value is Author s reply: Thank you. This has been corrected. Please comment on the significant heterogeneity of 2-hour post morphine administration, using MAE method across studies, and include the hospital mortality and MACE rate in table 1 and 2 where available. Author s reply: Thank you. We did not add an exploration of the heterogeneity in this outcome, as it is an exception in the overall results, and do not believe this would significantly add to the discussion. We did not add the in-hospital mortality or the MACE rate in the tables, as we believe this will cause the tables to be too large and cumbersome to read. However, we are available to make these additions if the Editors deem this relevant. The paper has great improvement in its result presentation with the anti-platelet information included in the tables. Author s reply: Thank you. VERSION 3 REVIEW Rita Pavasini UO Cardiologia, Azienda Ospedaliero Universitaria di Ferrara, Ferrara, Italy. 29-Dec-2018

15 REPLY TO 2 I have no other questions. Irene SL Zeng istatdome online datalab and Counties Manukau Health New Zealand 14-Jan-2019 I had a read of the reference paper 27, "Combining randomized and non randomized evidence in network meta analysis", which is quoted in the statistical analysis. The precision correction factor used in the analysis is referred to the weight in table II of the paper using a Bayesian approach. The confidence intervals therefore shall be the credible intervals, I am not sure where the results were presented. I suggest to have a second opinion for reviewing the statistical analysis. VERSION 3 AUTHOR RESPONSE Thank you for accepting our answers to the previous comments. REPLY TO 4 We thank the reviewer for the question raised. However, we are confident that the concern of the reviewer does not apply to this case. The reason is that the paper by Efthimiou et al refers to combining random and observational data in the context of a network meta-analysis, an analysis which most frequently is done with Bayesian statistics. As such, the results in Table 2 of the referenced paper are presented as credibility intervals and not confidence intervals. In our case, no network meta-analysis or Bayesian statistics were used and therefore our results should not be presented using credibility intervals. The reason why we referenced the work by Efthimiou et al, as suggested by these authors, was to use be conservative when combining data from observational studies with a high risk of bias. To do this, and following the suggested by Efthimiou et al, we applied the weight-correction factor to studies at a critical risk of bias. In conclusion, we believe that our approach is conservative and correct as the meta-analysis we conducted should not use credibility intervals.