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I am writing to inform you that your manuscript - Efficacy and safety of rivaroxaban in neonatal catheter-related thrombosis: a single-center retrospective study of 122 cases - has been Accepted for publication. Congratulations!
[# PeerJ Staff Note - this decision was reviewed and approved by Celine Gallagher, a PeerJ Section Editor covering this Section #]
Title & Abstract
The study's title shows its focus. The abstract explains the study's goals well, which are finding the risk factors and checking how safe and effective rivaroxaban is for treating thrombosis in newborns with catheters. The methods section gives a summary of the statistical methods and the main result (complete thrombus resolution). The results section within the abstract reports no bleeding complications, and gives specific rates of clot resolution. It also points out chemotherapy and difficult catheter placement as risk factors. The conclusion matches the study's results.
The title and abstract are acceptable. No changes were suggested in this revision.
Introduction
By clearly describing the clinical issue of VTE in neonates, the function of CVCs as a risk factor, and the drawbacks of conventional heparin-based treatments, the introduction offers a solid foundation for comprehending the research. It gives the context for rivaroxaban research by citing significant guidelines and relevant incidence data. The earlier recommendations have already been implemented.
Figures & Tables
The authors have corrected Table 1 and Table 2 as advised. No further changes are suggested.
Material and Methods
The methodology is sound. This well-structured section provides a clear summary of the study design, population, intervention, data collection, and statistical analysis. There is adequate coverage of rivaroxaban administration, ultrasound follow-up, inclusion/exclusion criteria and statistical methods. No changes were suggested in this revision.
Results
The results are new because this is the first study to systematically evaluate the safety and efficacy of rivaroxaban specifically for neonatal CRT. The identification of chemotherapy, the difficult catheter placement, and the high complete thrombus resolution rates as independent risk factors for reduced efficacy provide new insights into neonatal anticoagulation.
Discussion
The findings, which include thrombus resolution rates, risk factors, and safety outcomes, strongly correlate with the results. The study's novelty as the first systematic assessment of rivaroxaban in neonatal CRT, backed by risk factor analysis and high resolution rates, is highlighted in the discussion. The suggested risk factor mechanisms are biologically tenable and offer a comprehensive comparison with spontaneous resolution. The discussion section is adequate and doesn't require any revisions.
Conclusion
The conclusion section aptly summarizes the key findings of the study and is satisfactory. No changes are suggested.
The manuscript is now written with clear language.
The authors described research with sufficient data and information.
In my opinion, data from the study show clinical impact for physicians.
Results are well-released, and findings from statistical analysis can help in understanding the results and making a conclusive statement.
All criteria addressed and fulfilled.
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This is the second revision of the manuscript entitled ''Efficacy and Safety of Rivaroxaban in Neonatal Catheter-related Thrombosis: A Single-center Retrospective Study of 122 Cases'' by Zhang et al. After reading the revised manuscript and rebuttal letter provided by the authors, I conclude that the manuscript was thoroughly revised and significantly improved. The anticoagulant therapy in neonates with CRT is a major clinical burden, and having at least the results of a retrospective study could represent a significant help to clinicians managing this disease.
As I do not have any additional concerns regarding this manuscript, I endorse this manuscript for publication in PeerJ.
Title & Abstract
The title was not suggested to be revised and thus, is carried from the previous version.
The authors have made all the changes in the abstract as requested. No further changes are suggested.
Introduction
The authors have made all the changes suggested in the previous version of the manuscript, and there are no further changes suggested in the introduction.
Figures & Tables
Table 1 is accurate except for the prematurity “no” count, which is a clear typographical error (16 vs. 107). Table 2 aligns with the text but contains redundant data for “Site of CRT” and “Catheter position.” Clarification or removal of the redundant category is needed to ensure clarity.
Material and Methods
The authors have incorporated the changes suggested, and the revised methods section does not need further changes.
Results
The authors have incorporated the changes suggested, and the revised results section does not need further changes.
Discussion
The revised Discussion section is satisfactory and does not need further changes.
Conclusion
The new conclusion section is satisfactory.
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The authors provided numerous and available references. Figures and tables of the manuscript are clear and structured.
The design of the study is well defined, and it meets the results.
There is a large interest in the question of medical anti-thrombotic therapy of venous thromboembolism in newborns and children. In addition, it is widely debated what links the use of venous catheters in treating young patients affected by venous thrombosis.
The direct oral antithrombotic agents such as rivaroxiban focused on by the study could represent a very intriguing challenge to treat venous thromboembolism occurred to pediatric patients.
In my opinion, the results of the retrospective study may be considered interesting for physicians.
Authors are requested to provide information on the efficacy or consequences of the rivaroxiban when compared to other anti-thrombotic drugs such as LMWH.
In my opinion, the requested comparison will improve the quality and novelty of the very interesting results released from the study.
The manuscript is written clearly, and comprehensive language was used. It is worth noting that authors report using AI tools to improve the quality of language; it is much appreciated that authors openly state the use of AI tools.
Appropriate literature was used to provide an adequate background for the research topic.
The article is structured appropriately, and raw data was shared. Figures and tables are good.
Experimental design is well-thought-out.
Original ethical approval for the study in the Chinese language was provided, but I am not sure if a certified English translation of this approval was provided, based on the PDF saved photography authors attached to the supplemental data. Authors should consult the Journal Editor to check for compliance with Journal rules.
Please clarify the following:
1. Table 3: Based on the presented results, the majority of patients had complete resolution after 6 weeks of anticoagulation therapy (71.31%). About 27% of patients had partial resolution. After 3 months of anticoagulants, this number increases to 88.52%. The interpretation of the results is misleading, as anticoagulant therapy was not continued in the group of patients who had their clots resolved after 6 weeks.
Please provide a separate analysis of patients at 6 weeks (87 patients) and 3 months (35 patients). The current analysis is not appropriate, as patients who had their clots resolved at 6 weeks are included in the group with the patients who had their clots resolved at 3 months.
Comments for the authors:
1. One of the exclusion criteria is: concurrent serious illness requiring additional treatment. Based on this criterion, 21 neonates were excluded from the study. Please define what the concurrent serious illnesses are, as cancer patients receiving chemotherapy and other surgical patients were included in the study, so to me, this criterion seems ill-defined.
2. In May 2025, ASH/ISTH published updated guidelines for the treatment of venous thromboembolism in pediatric patients (doi: 10.1182/bloodadvances.2024015328). Authors should update their Background and Discussion sections in the context of these new guidelines.
Title & Abstract
Title:
The study's focus is properly conveyed in the title. The drug, condition, design, and sample size are specified, all of which are suitable for indexing and reader interest.
Abstract:
The abstract (Page 6, Lines 33–50) is organized effectively and gives a concise synopsis of the study's history, methodology, findings, and conclusions. It briefly describes the study's objectives, which include determining risk factors and assessing rivaroxaban's safety and effectiveness in treating neonatal catheter-related thrombosis (CRT). The methods section provides an overview of the statistical methodology (multivariate logistic regression), the primary outcome (complete thrombus resolution rate), and the retrospective analysis of 122 patients. The results section shows the absence of bleeding complications, provides specific resolution rates (71.31% at 6 weeks, 88.52% at 3 months, p<0.01), and identifies chemotherapy and challenging catheter placement as risk factors with odds ratios and confidence intervals. The conclusion supports the study's findings, emphasizes rivaroxaban's possible safety and efficacy, and notes the need for additional research. However, I suggest the following to improve completeness and clarity:
1) The abstract mentions chemotherapy and difficult catheter placement as risk factors but does not clarify that these affect 3-month outcomes specifically, which could confuse readers about the timing of their impact. Revise the sentence to specify that chemotherapy and difficult catheter placement affect 3-month anticoagulation efficacy. For example, on Page 6, Line 43, replace "affecting 3-month anticoagulation efficacy" with "reducing the likelihood of complete thrombus resolution at 3 months" to make the impact clearer. Replace the next sentence (line 44) with “No anticoagulation-related bleeding or other complications were observed during the study period, though the sample size and follow-up period may limit detection of rare events”.
2) While the conclusion mentions the need for multi-center, prospective trials, explicitly noting the single-center, retrospective design as a limitation within the abstract would provide better context for generalizability. Replace the last sentence of the conclusion with “These findings, derived from a single-center retrospective study, require validation through multi-center, prospective, randomized controlled trials”.
Introduction
The introduction provides a robust background for understanding the research, effectively outlining the clinical problem of VTE in neonates, the role of CVCs as a risk factor, and the limitations of traditional heparin-based therapies. It provides the background for researching rivaroxaban by referencing important guidelines (2012 ACCP, 2018 ASH) and pertinent incidence statistics (e.g., 2.4–38 cases per 1,000 NICU admissions. By emphasizing the EINSTEIN-Jr trial's limitation of not defining neonatal inclusion, the introduction argues for the necessity of neonatal-specific data. Lines 78–80 make it clear that the study's objective is to assess the risks and real-world effects of rivaroxaban.
Suggestions for improvement:
1) Discuss Neonatal CRT Incidence and Burden in More Detail (Page 6, Lines 59–60). Although the range of 2.4 to 38 cases per 1,000 NICU admissions mentioned in the introduction is accurate, it could be supported by more recent data or clinical impact (e.g., morbidity, mortality). The urgency of the study is justified by the fact that neonatal CRT can result in complications such as post-thrombotic syndrome or pulmonary embolism. To emphasize these repercussions, add a sentence after Line 60: “Neonatal CRT is associated with significant morbidity, including risks of pulmonary embolism and post-thrombotic syndrome, underscoring the need for effective and safe anticoagulation therapies”.
2) To put the study population in context, the introduction could briefly discuss other neonatal CRT risk factors, such as prematurity, sepsis, and congenital heart disease, even though it focuses on CVCs as a risk factor. To expand the context, add a sentence after Line 64: "The risk of neonatal CRT is further increased by additional factors, including prematurity, sepsis, and congenital heart disease, which calls for targeted therapeutic approaches".
3) The EINSTEIN-Jr trial is mentioned in the introduction, but it is not mentioned that rivaroxaban was approved by the FDA in December 2021 for paediatric VTE, including neonates. This would support the case for researching its practical use in newborns. To make this clear, put a sentence after Line 74: "The USFDA approved rivaroxaban in December 2021 for paediatric VTE, including in neonates, following the EINSTEIN-Jr trial; however, there is still a lack of real-world evidence specifically related to neonatal CRT".
4) The authors cited old ASH guidelines from 2018. New guidelines have been published in 2024. Please refer them.
Figures & Tables
The PDF document does not have tables and figures.
Material and Methods
The study design, population, intervention, data collection, and statistical analysis are all clearly summarized in this well-organized section. The inclusion/exclusion criteria, rivaroxaban administration, ultrasound follow-up, data collection variables, statistical methods, and ethical approval are all sufficiently covered. Nonetheless, there are some places where more information, explanations, or arguments could improve readability, reproducibility, and resolve possible methodological issues. I address each of the requested aspects below:
1) Report the total number of neonates admitted during the study period to contextualize the 122 cases. Use this text: “This single-center retrospective study included 122 neonates with CRT out of [X] total neonates admitted to Fujian Provincial Maternal and Child Health Hospital between March 2022 and October 2024”.
2) The term "weight-adjusted doses" (Line 95) is vague, as no specific dosing regimen (e.g., mg/kg/day, frequency) is provided, which is critical for understanding the intervention.
3) The ultrasound examination process (Line 96) lacks details on standardization. The authors can use this statement: “Ultrasound examination was performed by trained radiologists using a standardized high-frequency linear probe, with assessments at baseline and 6 weeks to evaluate thrombus size and blood flow”.
4) The criteria for extending treatment to 3 months if the thrombus persists (Line 96) are not clearly defined (e.g., partial resolution, no resolution, or progression). If the authors agree, this line could be added: "Treatment was discontinued if thrombus resolved completely or extended to 3 months if partial resolution, no resolution, or progression was observed".
Results
Since this study is the first to systematically assess rivaroxaban's safety and effectiveness specifically for neonatal CRT, the findings are novel. New information about neonatal anticoagulation is provided by the high complete thrombus resolution rates, the identification of chemotherapy (OR=5.48–6.05), and the challenging catheter placement (OR=12.53) as independent risk factors for decreased efficacy. Previous studies, such as the EINSTEIN-Jr trial, included pediatric CRT but lacked neonatal-specific data, particularly for CRT, making this study a pioneering contribution to a gap in the literature.
There are minor concerns:
1) Provide the total number of neonates admitted to the NICU during the study period to contextualize the 376 CRT cases. Add on line 123 “During the study period, a total of 376 neonates developed catheter-related thrombosis out of [X] neonates admitted to the NICU”.
2) If available, present resolution rates by catheter type (CVC, PICC, PORT) or primary diagnosis (e.g., gastrointestinal vs. circulatory disorders) to explore heterogeneity. Add after the sentence mentioning “complete resolution rate significantly improved” at line 156.
3) Lines 161,168: The authors should mention what all factors were considered in the multivariate analysis and list the ones not significant.
4) Line 163: The phrase “6.05-fold higher risk of CRT” should clarify that it refers to reduced anticoagulation efficacy, not increased CRT incidence. Use this sentence: “Patients receiving chemotherapy demonstrated a 6.05-fold higher risk of persistent thrombosis compared to those without chemotherapy (OR=6.05, 95% CI: 1.32–28.49, P=0.02)”.
Discussion
The results, such as thrombus resolution rates, risk factors, and safety outcomes, are closely correlated with the findings discussed in the discussion. These findings are also pertinent to the goals of the study and the larger context. The study's novelty as the first systematic assessment of rivaroxaban in neonatal CRT (Line 177), backed by strong resolution rates and risk factor analysis, is highlighted in the discussion. The suggested mechanisms for risk factors (cytokine-induced coagulation in chemotherapy, vascular damage in difficult catheter placement, Lines 243–250) are biologically plausible, and they offer a comprehensive comparison with spontaneous resolution and other anticoagulation studies (Lines 197–227).
There are minor concerns:
1) On line 212, the authors should add a sentence to compare rivaroxaban’s resolution rates to those of LMWH or unfractionated heparin from prior neonatal studies to contextualize efficacy. For example – “Although direct comparisons are not feasible, these resolution rates substantially exceed the spontaneous resolution rates reported in existing literature and compare favorably to LMWH, which achieved …………”
2) While discussing the clinical implications, the authors can also mention that “Given its high resolution rates and low bleeding risk, rivaroxaban may represent a viable alternative to LMWH, potentially warranting consideration in future neonatal CRT treatment guidelines, pending prospective validation” at line 217 after the sentence ends.
3) On line 257, after the sentence ends, the authors can add “This limitation underscores the need for prospective studies with extended follow-up to evaluate long-term outcomes, such as post-thrombotic syndrome and recurrent VTE, which significantly impact neonatal health”.
Conclusion
I suggest replacing the existing text with the following to enhance clarity: “Retrospective data from a single-center study suggest that rivaroxaban is potentially safe and effective in treating neonatal catheter-related thrombosis, though the small sample size and short follow-up may limit detection of rare complications, with a higher complete thrombus resolution rate observed at 3 months compared to 6 weeks of anticoagulation therapy. Chemotherapy and difficult catheter placement were identified as independent risk factors affecting treatment efficacy. These findings position rivaroxaban as a potential alternative to low-molecular-weight heparin, warranting consideration in future neonatal CRT treatment guidelines. Further studies are needed to assess long-term outcomes, such as post-thrombotic syndrome and recurrent VTE, through multi-center, prospective, randomized controlled trials.”
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