Comparison of short-term clinical outcomes between low-dose prasugrel and clopidogrel as part of triple antithrombotic therapy in patients requiring oral anticoagulant therapy and percutaneous coronary intervention

Hideki Kitahara; Kazuya Tateishi; Yuki Shiko; Yusuke Inaba; Yoshio Kobayashi; Takahiro Inoue

doi:10.1371/journal.pone.0272140

Peer Review History

Original SubmissionApril 29, 2022
17 Jun 2022 Decision Letter - R. Jay Widmer, Editor PONE-D-22-12588Comparison of short-term clinical outcomes between low-dose prasugrel and clopidogrel as part of triple antithrombotic therapy in patients requiring oral anticoagulant therapy and percutaneous coronary interventionPLOS ONE Dear Dr. Kitahara, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== The reviewers have viewed your article in a mostly positive light, however still have some concerns. Please address these concerns in an individual fashion in your rebuttal letter. ============================== Please submit your revised manuscript by Aug 01 2022 11:59PM. 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If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” c) If any authors received a salary from any of your funders, please state which authors and which funders. d) If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. [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? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: I Don't Know ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: In the ESC guideline, the combination of clopidgrel and DOAC as a part of triple antithrombotic therapy has been recommended to treat patients who need both OAC therapy and PCI procedure. However, in the guideline, the combination therapy of prasgrel and DOAC has not been indicated in such patients because of higher rates of adverse events including bleeding ones. On the contrast, Japanese GL recommends 3.75mg/day doses of prasgrel in addition to ASA+DOAC to treat Japanese patients with same conditions. However, until now, there has been limited data to show the efficacies of the regimen. The authors clearly showed safety and efficacy of combination of low-dose prasugrel and DOAC as a part of triple antithrombotic therapy, and the regimen was associated with lower incidence of events compared to combination of clopidgrel and DOAC. The study included a large number of patients and the results are reasonable and promising and are of significance in the clinical practice. The reviewer has some queries as shown below. Specific comments 1. TTR was not evaluated in patients treated with VKA. This seems a limitation. 2. Please specify the dose of ‘standard-dose’ of prasugrel. But this may mean the dose for Western countries. Please add some explanation. In addition, in Japan, much lower doses of prasugrel (2,5mg/day) may be used in patients with some specific conditions. 3. Did the authors include potassium-competitive acid blockers into PPI as the criteria? Please clarify. PPI might be much more highly prescribed compared to Western countries. This may be one of the reason why such a low rate of GI bleeding was seen in the study. Please add some comments. Reviewer #2: The study aims to look at low dose prasugrel as part of triple therapy. 1) What is the rational for the low dose prasugrel in Japan? You provide BMI but not weight. If this population weight less compared to western population, perhaps the low dose prasugrel is not low? Further, there is 5 mg available / used elsewhere 2) What is the reason for the high use of VKA? I understand you don’t have details, but this is quite high, as you mention in introduction that only certain patients such as mechanical valve require VKA 3) The study is likely not powered for primary outcome of death 4) What about outcome post discharge 5) The Figure 2 is hard to read due to poor resolution ****** 6. PLOS authors have the option to publish the peer review history of their article (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: Hideki ISHII Reviewer #2: No ******** [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. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0272140.r001
Revision 1
7 Jul 2022 Author Response Reviewer #1: We would like to thank you for your careful review of our manuscript. We have revised our manuscript to incorporate your recommendations as fully as possible. Responses to the specific points are given below. Comment #1: TTR was not evaluated in patients treated with VKA. This seems a limitation. Authors’ Response to Comment #1: Thank you very much for this important comment. In the revised manuscript, we have added the sentence “the database used in the present study did not include the time in therapeutic range in patients treated with VKA, which might be associated with clinical outcomes.” in the Limitation section (Page 14, Line 2-4). Comment #2: Please specify the dose of ‘standard-dose’ of prasugrel. But this may mean the dose for Western countries. Please add some explanation. In addition, in Japan, much lower doses of prasugrel (2,5mg/day) may be used in patients with some specific conditions. Authors’ Response to Comment #2: According to the reviewer’s suggestions, we have added the sentences explaining ‘standard-dose’ of prasugrel in Western countries, and ‘low-dose’ of prasugrel in Japan and some Asian countries in the Introduction section (Page 4, Line 12-13 and Line 17). In addition, much lower dose of prasugrel (2.5 mg/day) was used in 0.1% of patients (4/2,815 patients) in this study. This result was described in the Results section (Page 7, Line 20-22). Comment #3: Did the authors include potassium-competitive acid blockers into PPI as the criteria? Please clarify. PPI might be much more highly prescribed compared to Western countries. This may be one of the reason why such a low rate of GI bleeding was seen in the study. Please add some comments. Authors’ Response to Comment #3: We appreciate this meaningful comment. In the present study, potassium-competitive acid blockers were included in PPI. The criteria were described in the Methods section in the revised manuscript (Page 6, Line 19). In addition, the sentences regarding the low rate of GI bleeding were added in the Discussion section, as shown below. “In terms of gastrointestinal bleeding, the incidence was quite low, and no significant difference was observed among the 4 subgroups. In this study population, PPI was administered in around 80-85% of patients. This high frequency of PPI administration might be associated with the reduced incidence of gastrointestinal bleeding.” (Page 11, Line 25 – Page 12, Line 4) Thank you very much again for the time you have taken with our manuscript. We believe that incorporation of your suggestions significantly strengthened this manuscript. Reviewer #2: We would like to thank you for your careful review of our manuscript. We have revised our manuscript to incorporate your recommendations as fully as possible. Responses to the specific points are given below. Comment #1: What is the rational for the low dose prasugrel in Japan? You provide BMI but not weight. If this population weight less compared to western population, perhaps the low dose prasugrel is not low? Further, there is 5 mg available / used elsewhere Authors’ Response to Comment #1: Thank you very much for the meaningful comments. Body weight in this population was approximately 63kg, which seems to be much lower than that in Western countries (Table 1). When considering clinical introduction of prasugrel in Japan, special emphasis was placed on determining the dose to reduce the risk of bleeding events, because Japanese patients were considered to be older and have lower weight compared with Western patients. Dose-finding studies were carefully conducted, and randomized controlled trials confirmed the efficacy and safety of prasugrel 20/3.75 mg/day versus clopidogrel 300/75 mg/day in ACS patients as well as stable CAD patients undergoing PCI. These sentences were added in the Discussion section (Page 10, Line 18-23). Comment #2: What is the reason for the high use of VKA? I understand you don’t have details, but this is quite high, as you mention in introduction that only certain patients such as mechanical valve require VKA Authors’ Response to Comment #2: We appreciate this important comment. In the present study, the frequency of patients receiving VKA as part of triple therapy was relatively high (44%). Previously, the ANAFIE registry, with more than 30,000 Japanese patients, reported that 28% of AF patients on anticoagulant therapy received VKA (Eur Heart J Qual Care Clin Outcomes. 2022;8:202-13). The present study included every patient on anticoagulant therapy. Therefore, some patients with specific conditions requiring VKA (e.g. mechanical valve, some types of thrombosis like left ventricular thrombosis, autoimmune disease, such as antiphospholipid syndrome) must have been included. This might be able to explain the high prevalence of VKA, although the database used in the present study did not have the information about actual indication for VKA or DOAC. These sentences were added in the Discussion section (Page 12, Line 24 – Page 13, Line 7). Comment #3: The study is likely not powered for primary outcome of death Authors’ Response to Comment #3: We appreciate this important comment. In response, we have mentioned about this issue in the Limitation section: “sample size calculation was not conducted for the primary outcome of in-hospital death because of the retrospective nature of this study”. (Page 13, Line 16-18). Comment #4: What about outcome post discharge Authors’ Response to Comment #4: Clinical outcomes post discharge were not evaluated in this analysis. Thus, we clearly mentioned about this issue in the Limitation section (Page 13, Line 18-19). Comment #5: The Figure 2 is hard to read due to poor resolution Authors’ Response to Comment #5: Thank you for the comment. The resolution of Figure 2 was increased in the revised manuscript. Thank you very much again for the time you have taken with our manuscript. We believe that incorporation of your suggestions strengthened this manuscript. Attachments Attachment Submitted filename: Response to Reviewers_20220707.docx https://doi.org/10.1371/journal.pone.0272140.r002
14 Jul 2022 Decision Letter - R. Jay Widmer, Editor Comparison of short-term clinical outcomes between low-dose prasugrel and clopidogrel as part of triple antithrombotic therapy in patients requiring oral anticoagulant therapy and percutaneous coronary intervention PONE-D-22-12588R1 Dear Dr. Kitahara, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. 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, R. Jay Widmer Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: I Don't Know ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: No ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: No ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Thank you for changings. The manuscript has been significantly improved. The reviewer has no criticism. Reviewer #2: (No Response) ****** 7. PLOS authors have the option to publish the peer review history of their article (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: Hideki Ishii Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0272140.r003
Formally Accepted
18 Jul 2022 Acceptance Letter - R. Jay Widmer, Editor PONE-D-22-12588R1 Comparison of short-term clinical outcomes between low-dose prasugrel and clopidogrel as part of triple antithrombotic therapy in patients requiring oral anticoagulant therapy and percutaneous coronary intervention Dear Dr. Kitahara: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. R. Jay Widmer Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0272140.r004

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