Smaller infarct size with ticagrelor vs. clopidogrel in STEMI patients: Insights from cardiac magnetic resonance

Francisco A Fonseca; Adriano Caixeta; Gilberto Szarf; Ibraim Pinto; Antonio M Figueiredo Neto; Carolina N França; Henrique T Bianco; Henrique A Fonseca; Amanda S Bacchin; Michelle Birtche; Igor R M Batista; Maria C Izar; for the BATTLE-AMI investigators

doi:10.1371/journal.pone.0328114

Peer Review History

Original SubmissionJuly 1, 2025
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If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 7. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: The manuscript presents a well-designed randomized clinical trial comparing the effects of ticagrelor and clopidogrel on infarct size in STEMI patients managed with a pharmaco-invasive strategy. The manuscript is technically robust. The study design adheres to rigorous clinical trial standards. The data strongly support the primary conclusion that ticagrelor is associated with a smaller infarct size compared to clopidogrel in STEMI patients, including the primary outcome of a significantly smaller percentage of left ventricular infarcted mass (p=0.012), with consistent results in both absolute (grams) and relative (%) measurements. Despite similar baseline angiographic characteristics (Syntax score, TIMI flow, culprit artery distribution) and post-PCI reperfusion success, the ticagrelor group showed more homogeneous responses (via K-means clustering) with smaller infarct sizes and better LVEF. Lower high-sensitivity troponin T (hsTNT) and high-sensitivity C-reactive protein (hsCRP) on day 1 in the ticagrelor group suggest early benefits on microcirculation, reinforcing the mechanistic link to reduced infarct size. Confounding variables (e.g., lipid profiles, other inflammatory markers) were balanced between groups, strengthening the causal inference. The statistical approach is rigorous and appropriate for the study design. The manuscript is well-structured and written in clear, standard English. Tables and figures are informative and support the narrative, though legends could be slightly expanded to clarify statistical significance markers for non-specialist readers. The study is limited to STEMI patients <75 years without prior myocardial infarction, managed via a pharmaco-invasive strategy. Caution is advised when extrapolating to primary PCI populations, which the authors appropriately note in limitations. The discussion links ticagrelor's benefits to improved microcirculation (via adenosine uptake inhibition) and reduced inflammation, supported by prior literature. Expanding on how improved LDL quality (cited in ref. 39) might contribute to long-term outcomes could strengthen the mechanistic narrative. While the sample (n=225) is sufficient to detect differences in infarct size, larger trials are warranted to validate these findings, as acknowledged in the conclusion. This manuscript is methodologically sound, with robust data supporting its conclusions. The rigorous design, appropriate use of CMR, and thorough statistical analysis make it a valuable contribution to understanding antiplatelet therapy in STEMI. Minor refinements to mechanistic discussions and generalizability notes would further enhance its impact. We recommend consideration for publication. Reviewer #2: Interesting paper. Some issues should be addresed Major Do authors think that these fidngins hold true for patients treated with pPCI without thrombolysis? Time of enrollement compared to number of patients appears long. Please comment Abstract: please add numeric values for the area at risk Recently lenght and kind of DAPT demonstrated to change prognosis. Please relate your findings with those from a clinical point of view (quote on PMID: 38242567) ****** what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy Reviewer #1: Yes: Dong Huang Reviewer #2: Yes: Fabrizio D'Ascenzo ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org https://doi.org/10.1371/journal.pone.0328114.r001
Revision 1
27 Aug 2025 Author Response Responses to reviewers Reviewer #1: The manuscript presents a well-designed randomized clinical trial comparing the effects of ticagrelor and clopidogrel on infarct size in STEMI patients managed with a pharmaco-invasive strategy. The manuscript is technically robust. The study design adheres to rigorous standards for clinical trials. The data strongly support the primary conclusion that ticagrelor is associated with a smaller infarct size compared to clopidogrel in STEMI patients, including the primary outcome of a significantly smaller percentage of left ventricular infarcted mass (p = 0.012), with consistent results in both absolute (grams) and relative (%) measurements. Despite similar baseline angiographic characteristics (Syntax score, TIMI flow, culprit artery distribution) and post-PCI reperfusion success, the ticagrelor group showed more homogeneous responses (via K-means clustering) with smaller infarct sizes and better LVEF. Lower high-sensitivity troponin T (hsTNT) and high-sensitivity C-reactive protein (hsCRP) on day 1 in the ticagrelor group suggest early benefits on microcirculation, reinforcing the mechanistic link to reduced infarct size. Confounding variables (e.g., lipid profiles, other inflammatory markers) were balanced between groups, strengthening the causal inference. The statistical approach is rigorous and appropriate for the study design. The manuscript is well-structured and written in clear, standard English. Tables and figures are informative and support the narrative, though legends could be slightly expanded to clarify statistical significance markers for non-specialist readers. Authors: We added information in the legend of figure 2. Figure 2. Box plots illustrating differences between the ticagrelor and clopidogrel groups on the first day of myocardial infarction. A – High-sensitivity troponin (hsTNT); B – High-sensitivity C-reactive protein (hsCRP). Lower levels of hsTNT and hsCRP were observed among patients treated with ticagrelor compared to those treated with clopidogrel (Mann-Whitney test). The study is limited to STEMI patients <75 years without prior myocardial infarction, managed via a pharmaco-invasive strategy. Caution is advised when extrapolating to primary PCI populations, which the authors appropriately note in limitations. The discussion links ticagrelor's benefits to improved microcirculation (via adenosine uptake inhibition) and reduced inflammation, supported by prior literature. Expanding on how improved LDL quality (cited in ref. 39) might contribute to long-term outcomes could strengthen the mechanistic narrative. While the sample (n=225) is sufficient to detect differences in infarct size, larger trials are warranted to validate these findings, as acknowledged in the conclusion. This manuscript is methodologically sound, with robust data supporting its conclusions. The rigorous design, appropriate use of CMR, and thorough statistical analysis make it a valuable contribution to understanding antiplatelet therapy in STEMI. Minor refinements to mechanistic discussions and generalizability notes would further enhance its impact. We recommend consideration for publication. Authors: The authors appreciate your comments. We added minor refinements to mechanistic discussions and generalizability notes to improve the manuscript (see page 10, lines 352-359). In the PLATO study, the primary endpoint (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) was significantly reduced even in the period after the first 30 days up to one year1. These data suggest continued benefits in addition to those directly related to thrombosis or microcirculation during the acute phase of myocardial infarction. Our results were obtained in patients undergoing a pharmaco-invasive strategy, the only group of acute coronary syndrome patients not included in the PLATO study1. Reviewer #2: Interesting paper. Some issues should be addressed Major Do authors think that these findings hold true for patients treated with pPCI without thrombolysis? Time of enrollment compared to number of patients appears long. Please comment Abstract: please add numeric values for the area at risk Recently length and kind of DAPT demonstrated to change prognosis. Please relate your findings with those from a clinical point of view (quote on PMID: 38242567) Authors: We appreciate your comments. Do authors think that these findings hold true for patients treated with pPCI without thrombolysis? Authors: It is an important question (see page 10 lines 352-362). In the PLATO study, the primary endpoint (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) was significantly reduced even in the period after the first 30 days up to one year1. These data suggest continued benefits in addition to those directly related to thrombosis or microcirculation during the acute phase of myocardial infarction. Our results were obtained in patients undergoing pharmaco-invasive strategy, the only group of acute coronary syndrome patients not included in the PLATO study1. Later, in the TREAT trial10, the safety for bleeding in patients following pharmaco-invasive strategy was similar between those receiving ticagrelor or clopidogrel. However, the study did not have sufficient power to analyze major cardiovascular endpoints10. Therefore, for patients undergoing pharmaco-invasive strategy, despite promising data in our study, larger studies addressing cardiovascular outcomes are needed. Time of enrollment compared to number of patients appears long. Please comment Authors: In fact, we included patients from May 2015 to March 2020. This study is part of the BATTLE-AMI trial, a thematic study addressing the key players in the amount of infarcted mass and LVEF quantified by CMR. In the trial protocol we included only stable patients undergoing pharmacological thrombolysis in the first 6 hours of symptoms onset and referred to our university hospital in the first 24 hours for coronary angiography and invasive procedures. Based on the inclusion and exclusion criteria, we gradually reached approximately the planned number of patients only in March 2020. At this point, we had the challenge of the coronavirus epidemic and we decided to end the study. (see pages 3 lines 99-126). Abstract: please add numeric values for the area at risk Recently length and kind of DAPT demonstrated to change prognosis. Please relate your findings with those from a clinical point of view (quote on PMID: 38242567) Authors: unfortunately we did not measure the area at risk by CMR, however the groups were comparable for both pre- and post-PCI, and for most clinical and laboratory data. Area at risk is an important topic and we will include it in future manuscripts using a new software for this analysis. The length and kind of DAPT is really a very important issue. We added two recent meta-analyses addressing bleeding rates and ischemic events among ACS patients with de-escalation of DAPT. (see page 10,11, lines 364-372; ref 40 and 41). More recently, DAPT strategies and de-escalation after 1-3 months have been examined. First, a comparison of six antiplatelet strategies in ACS patients undergoing PCI was reported, showing lower bleeding rates with de-escalation of DAPT without increase in stent thrombosis40. Further, meta-analysis of six trials showed that compared with 12-months of DAPT, de-escalation (after 1-3 months of DAPT), with ticagrelor as a single antiplatelet agent, reduced bleeding rates and did not increase ischemic events. In fact, DAPT de-escalation was associated with decrease in cardiovascular and all-cause mortality41. The authors appreciate your valuable comments. Attachments Attachment Submitted filename: Responses to reviewers.docx https://doi.org/10.1371/journal.pone.0328114.r002
14 Sep 2025 Decision Letter - Shukri AlSaif, Editor Smaller Infarct Size with Ticagrelor vs. Clopidogrel in STEMI Patients: Insights from Cardiac Magnetic Resonance PONE-D-25-30655R1 Dear Dr.Francisco A H Fonseca, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Shukri AlSaif Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewer #2: Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #2: Yes ****** Reviewer #2: All comments have been addressed and authors should be complimented for addressing such a relevant issues. ****** what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy Reviewer #2: Yes: Fabrizio D'Ascenzo ******** https://doi.org/10.1371/journal.pone.0328114.r003
Formally Accepted
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