Amlodipine Therapy in β-Thalassemia Patients: A Systematic Review and Meta-Analysis on Ferritin Levels and Liver MRI T2*

Round 1

Reviewer 1 Report

Introduction is quite well written with all the information regarding β-thalassemia and amlodipine. In Methods it is described with a clear way the statistical analysis and the meta-analysis of the studies revelant to amlodipine and β thalassemia. In results only 7 studies fullfil the criteria for the recommendation of adding amlodipine in thalassemic patients. Possibly a cardiac MRI T2* apart fron liver MRI T2* would be useful for this observation of adding amlodipine. The review of the studies in the multivariate meta-analysis provide the conclusion of reduction of serum ferritin in patients receiving amlodipine plus chelation. In discussion the review of the literature is detailed and sufficiently proposed. In general, the number of studies that provide evidence of adding amlodipine in this group of patients is very low. Reduction of ferritin levels it is provided by 7 studies and for improving liver ΜRI T2* are just 2 studies. The low evidence of the results regarding the 7 studies is also mentioned by the authors. But maybe this observation and recommendation from these studies it is a reason for publication and a occasion for large prospective studies for the role of amlodipine in β thalassemic patients

Moderate changes

Author Response

Date: 2023-12-02

Subject: Reply to the Reviewers’ Comments

Thalassemia Reports

Title: Amlodipine Therapy in β-thalassemia Patients: A Systematic Review and Meta-Analysis on Ferritin Levels and Liver MRI T2*

Manuscript ID: thalassrep-2711779

Dear Editors

I do appreciate the encouragement of this manuscript by the reviewers. The authors have provided a point-by-point reply based on the reviewer's comments. We also hope that the revised manuscript has been achieved to the journal standards (Thalassemia Reports). Moreover, the manuscript was edited by a native English speaker. As well as that, the similarities were addressed. We submitted the revised manuscript with the reply to reviewers' comments as point by point.

Reviewer's Comments #

# Reviewer 1

Open Review

( ) I would not like to sign my review report
(x) I would like to sign my review report

Quality of English Language

( ) I am not qualified to assess the quality of English in this paper
( ) English very difficult to understand/incomprehensible
( ) Extensive editing of English language required
(x) Moderate editing of English language required
( ) Minor editing of English language required
( ) English language fine. No issues detected

Comments and Suggestions for Authors

Introduction is quite well written with all the information regarding β-thalassemia and amlodipine. In Methods it is described with a clear way the statistical analysis and the meta-analysis of the studies revelant to amlodipine and β thalassemia. In results only 7 studies fullfil the criteria for the recommendation of adding amlodipine in thalassemic patients. Possibly a cardiac MRI T2* apart fron liver MRI T2* would be useful for this observation of adding amlodipine. The review of the studies in the multivariate meta-analysis provide the conclusion of reduction of serum ferritin in patients receiving amlodipine plus chelation. In discussion the review of the literature is detailed and sufficiently proposed.

In general, the number of studies that provide evidence of adding amlodipine in this group of patients is very low. Reduction of ferritin levels it is provided by 7 studies and for improving liver ΜRI T2* are just 2 studies. The low evidence of the results regarding the 7 studies is also mentioned by the authors. But maybe this observation and recommendation from these studies it is a reason for publication and a occasion for large prospective studies for the role of amlodipine in β thalassemic patients

Comments on the Quality of English Language

Moderate changes

Submission Date

26 October 2023

Date of this review

13 Nov 2023 12:31:20

Response: Thank you so much for your comment. As the previous systematic review and meta-analysis implemented and reported data belonging to cardiac MRI T2*, we decided to remove that part from the study. The authors tried to mention the study limitations at the end of the conclusion, as well as providing several suggestions for future studies. Moreover, the manuscript was edited by a native English speaker. I hope the revised manuscript has met the Journal’s criteria.

Author Response File: Author Response.pdf

Reviewer 2 Report

1. In the introduction part a brief detail of different thalassemia syndromes should be added. 

2. Figure and diagrams are not of good quality. It should be of appropriate quality.

3. Table 1 presents the risk of bias evaluation in a methodical manner. Think about spending a few minutes talking about how the detected biases affect the overall quality of the evidence.

4. In the discussion part make a clear distinction between conclusions based on scant or preliminary data and those that are backed by substantial evidence. Since the document refers to a "very low level of evidence," it is imperative that the findings drawn be emphasized as being strong. Although the substantial degree of study heterogeneity is acknowledged, further exploration of the possible causes of heterogeneity and how it affects the findings is necessary.

5. Suggest areas for future research and discuss how future studies might address the limitations identified in the current systematic review

1. There are a lot of grammatical and punctuation errors in the manuscript, they should be properly addressed and rectified.

Author Response

# Reviewer 2

Open Review

(x) I would not like to sign my review report
( ) I would like to sign my review report

Quality of English Language

( ) I am not qualified to assess the quality of English in this paper
( ) English very difficult to understand/incomprehensible
(x) Extensive editing of English language required
( ) Moderate editing of English language required
( ) Minor editing of English language required
( ) English language fine. No issues detected

Comments and Suggestions for Authors

1. In the introduction part a brief detail of different thalassemia syndromes should be added. 

Response: Thank you for your comment. A summary of thalassemia syndromes has been added to the revised manuscript. Lines 62-66.

2. Figure and diagrams are not of good quality. It should be of appropriate quality.

Response: The figures’ resolution has risen to provide a better quality for the revised manuscript. Thank you.  

3. Table 1 presents the risk of bias evaluation in a methodical manner. Think about spending a few minutes talking about how the detected biases affect the overall quality of the evidence.

Response: We appreciate your comment. The authors attempted to improve the presentation of the risk of bias assessment in the revised manuscript. Your valuable remarks encouraged us to operate the quality and sensitive analyses to explore the cause of heterogeneity for the included studies. All changes have been highlighted in the revised manuscript.

Lines 173-177

Lines 228-244

Lines 253-256

Lines 288-290

4. In the discussion part make a clear distinction between conclusions based on scant or preliminary data and those that are backed by substantial evidence. Since the document refers to a "very low level of evidence," it is imperative that the findings drawn be emphasized as being strong. Although the substantial degree of study heterogeneity is acknowledged, further exploration of the possible causes of heterogeneity and how it affects the findings is necessary.

Response: Thank you so much for your comment. we tried to provide evidence supporting the results through both clinical and pre-clinical studies. All potential limitations influencing the results are thoroughly stated, which was followed by several recommendations for the future. Entire the manuscript, the authors write cautiously about the evidence to be interpreted by the readers properly. The changes and new sentences are highlighted in the revised manuscript.

Furthermore, upon running the quality analysis, we realized that the quality of studies was the source of heterogeneity, which is added to the results and discussion.

5. Suggest areas for future research and discuss how future studies might address the limitations identified in the current systematic review

The authors tried to mention the study limitations at the end of the conclusion, as well as providing several recommendations for future studies

Comments on the Quality of English Language

1. There are a lot of grammatical and punctuation errors in the manuscript, they should be properly addressed and rectified.

Submission Date

26 October 2023

Date of this review

23 Nov 2023 18:32:17

Response: We appreciate your time and attention. the manuscript was edited by a native English speaker. I hope the revised manuscript has met the Journal’s standards. Every change was highlighted in the revised manuscript.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

All the raised concerns have been addressed. I am satisfied by the author's responses.