PONE-D-20-14185

Incidence and risk factors for major bleeding among patients undergoing percutaneous coronary intervention: findings from the Norwegian Coronary Stent Trial (NORSTENT).

PLOS ONE

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PLOS ONE

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4.Thank you for including your ethics statement:  'NORSTENT (ClinicalTrials.gov: NCT0081177) has been approved by the Regional Ethics Committee

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Additional Editor Comments (if provided):

The authors report original results on predictors of bleeding events in the large NORSTENT cohort.

Data analysis shows no impact by the type of stent implantes (DES vs BMS) on bleeding. This is an important confirmation of previous results in a large study cohort that fit in the lane of previous evidence. A recent nationwide report (Giannini F. et al. Italian Multicenter Registry of Bare Metal Stent Use in Modern Percutaneous Coronary Intervention Era (AMARCORD): A multicenter observational study. Catheter Cardiovasc Interv. 2020 Mar 21. doi: 10.1002/ccd.28798. Online ahead of print.) showed a hyperbolic reducion in BMS use from 2013 to rates lower than 1% in 2016). This phenomenon depicts a trend that was sustanined by a growing body of evidence on the use of DES in different clinical context, including high bleeding risk patients. Please discuss this aspect.

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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

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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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: No

Reviewer #2: Yes

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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

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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 this manuscript, Samuelsen investigated potential risk factors of major bleeding in the Norwegian Coronary Stent Trial. More than 9000 patients were included into the randomized control trial and followed for a median of five years. The authors observed a cumulative incidence rate of 2.3%. Additional risk factors were also identified to relate to major bleeding such as CKD, underweight, diabetes and advanced age. Overall, the study is interesting and the manuscript was well written.

Following are some comments to be considered.

• The authors merged both study arms. However, it is unclear how many samples were assigned to each study arm. It would also be useful to compare the risk factors derived from either arm.

• In addition to MI, what other ischemic events were studied?

• Is there any control for medication?

• The authors indicated that “the combined proportion of missing observations was 17% with a missing at random pattern”. How the missing at random pattern was assessed?

• Is there any normalization of the study variables?

• How the baseline was defined for patients with multiple stent implanted? Was it counted since the last stent was implanted?

• Is there any bleeding prior to the stent implantation?

• In figure 1, please list the cumulative number of events under each year of follow-up

Reviewer #2: In the manuscript entitled "Incidence and risk factors for major bleeding among patients undergoing percutaneous coronary intervention: findings from the Norwegian Coronary Stent Trial (NORSTENT) " authors lead by Per-Jostein Samuelsen investigated the major bleeding risk factors in their cohort of 9013 patients.

This analysis shows chronic kidney disease (CKD), advanced age, and underweight as risk factors for major bleeding among patients receiving DAPT after PCI. Moreover, diabetes mellitus or recurrent MI increase bleeding risk during the follow-up.

The authors should be commended in their effort, as this analysis could support prior reports giving insights on this relevant problem. This reviewer has the following comments to raise with respect to the manuscript:

• Impact of the effective duration of DAPT is not presented in the document. Could the authors present this data, if available, and put it into perspective towards the effect of the various predictors? Is longer DAPT duration a predictor for bleeding in this analysis, could the author estimate the increase in bleeding each month of extended DAPT above 9 months?

• PCI or MI during follow-up increased risk of bleeding. This is probably due to extending DAPT after additional procedures and subsequent peri-procedural/intrahospital events. Was this adjusted for overall DAPT duration? If this is not the case this is not interesting and the text dedicated to this result shortened.

• BARC bleeding 3,4 or 5. Why the authors decided to also include BARC 4 in the primary endpoint ? This is hardly a marker of out-of hospital bleeding related to DAPT.

• It would be meaningful to present information on the bleeding sites.

• Was a treatment with clopidogrel made for all patients ? Or novel P2Y12 inhibitors have been also used ? If this is not the case this should be added in the limitation section.

• Could the authors validate PRECISE-DAPT score in their population? A validation of the DAPT score would not be feasible since most patients did not do more than 9 months of DAPT.

• Discussion section, for the PRECISE-DAPT please report the incidence of TIMI Major or minor bleeding, comparison between BARC 3 or 5 and TIMI major bleeding only would be misleading.

• The higher reported event rate could be also due to procedural characteristics than in 2008 -2011 were much different than today (e.g. bulkier access site, higher use of GPI). This should be reported in the study discussion and limitations.

• Discussion, diabetes. "This could lead to diabetic ulcerations of the feet, and retinopathy. 257 The latter could cause intraocular bleeding compromising vision, which is classified as a BARC major 258 bleeding [8]." Could the authors support this statement with prior data from the literature. If this is not the case the conclusion here seems farfetched. In addition, the rate of intraocular bleeding is very low and hardly explain alone the association of diabetes with bleeding.

• Abstract, row 7: the authors repeated the word “randomized” twice.

• Line 31: please state international guidelines: also Canadian guidelines and Japanese guidelines support standardized risk scores for DAPT.

• While citing Rothwell et al. wasn't the threshold used in that manuscript 70kg rather than 90 kg ?

• Supplementary Figure 1 is interesting. DAG is very informative and graphic. Could the authors please explain why older age, that is independently associated to major bleeding, also provide an effect through diabetes and CKD ? is this a clinical assumption or the product of analysis ?

• Figure 2 is really informative. However, I believe that the higher rates of bleeding presented in the first block (0 to 6 months) are driven by intrahospital/periprocedural bleeding (especially considering the practice in 2008-2011 in which femoral access and GPIIb/IIIa were more extensively used). Excluding those events from the analysis would be much more informative to provide a snapshot of the bleeding risk during therapy during out-of-hospital follow-up.

• Table 3 could be simplified shortened eliminating the reference lines. Information about the reference groups could be included in the rows or in the footnotes.

• Table 3 there is a typo for stent length >40mm (1.5q).

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Reviewer #1: No

Reviewer #2: No

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Incidence and risk factors for major bleeding among patients undergoing percutaneous coronary intervention: findings from the Norwegian Coronary Stent Trial (NORSTENT)

PONE-D-20-14185R1

Dear Dr. Samuelsen,

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.

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Kind regards,

Salvatore De Rosa

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

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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

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

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

**********

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

**********

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: (No Response)

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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: No