PONE-D-20-39776

ST-segment elevation myocardial infarction with non-obstructive coronary arteries: derivation of a score for prediction based on a large national registry

PLOS ONE

Dear Dr. Januszek,

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.

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We look forward to receiving your revised manuscript.

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Carmine Pizzi

Academic Editor

PLOS ONE

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5.We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

https://www.dovepress.com/characteristics-of-patients-with-myocardial-infarction-with-nonobstruc-peer-reviewed-article-VHRM

https://www.mdpi.com/2077-0383/9/11/3610/html

The text that needs to be addressed involves sections of the Introduction and Discussion.

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed."

Reviewers' comments:

Reviewer #1: In this paper Jędrychowska et al. create a MINOCA STEMI predictive score using the regression model, in order to distinguish, in STEMI group, MINOCA patients from MI-CAD patients; younger age, female gender, no history of prior CABG, no history of smoking, no arterial hypertension, presence of COPD, no treatment with 3rd generation P2Y12, no direct transport to hospital, Killip class I or II, no history of diabetes and greater body mass at admission were considered significant predictors of MINOCA among STEMI patients qualified for urgent coronary angiography and used to develop the score. The coefficients calculated were used to construct the predictive model in the form of a nomogram. The model showed that patients who scored more than 600 points had a 19% probability of MINOCA, and for patients scoring more than 650 points, the probability of MINOCA was 71%.

The study is interesting and focuses on a relatively new diagnostic problem such as the MINOCA patients. Nevertheless, I have some major concerns:

1) MINOCA diagnosis --> according to ESC Guidelines? --> how do you exclude the cases of non-ischemic troponin elevation? These patients are not MINOCA (3° point of ESC Position Paper).

2) There are no data on troponin. How was STEMI diagnosed?

3) Table 1: The majority of MINOCA patients with prior AMI, had also prior PCI --> so they supposed to have a significative CAD. How these patients could be classified as MINOCA?

4) Table 1: 67 patients classified as MINOCA had a previous CABG. The same as before, these patients had significative CAD. I suppose they are not MINOCA.

5) Table 2: “Considering patients from the MINOCA group, 71.57% had significant stenoses while 28.43% no visible atherosclerosis”. If these patients had significant CAD, why they are called MINOCA?

6) What was the cause of MINOCA? Is there any information for the prevalence of plaque disruption, coronary artery spasm, coronary thromboembolism, coronary dissection?

7) It is sufficient to approximate the numbers in the tables to the first decimal. Tables will be more readable.

8) 45% of MINOCA are in DAPT. In these patients, was DAPT therapy administered even without DES implantation?

9) The score assigned to each variable is not clear.

10) The main purpose is understanding how distinguish a priori a patient with MINOCA and possibly not to perform a coronary study. I believe that the results are absolutely not suitable for reaching this conclusion. Even if the score is > 650, the probability that it is a MINOCA is about 71%; therefore, it means that about 30% of patients are not MINOCA, actually; I don't think with these numbers it is possible to decide not to perform a CAG to a patient when it is recognized that an early PTCA can improve the prognosis. The criteria for performing a CAG as soon as possible (in STEMI) have been formulated precisely because they admit a low sensitivity and therefore provide for the possibility of having false positives with patients with free coronary arteries.

11) AUC 0.7 --> It seems to me little bit low.

Reviewer #2: M. Jędrychowska and coworkers studied the main clinical and angiography differences in a large population of STEMI in both obstructive acute myocardial infarction and MINOCA patients. Data were collected between January 2014 and December 2019, and were selected from 1,177,218 patients who underwent coronary angiography. The authors aimed to create a tool facilitating a rapid separation of the MINOCA patients from the entire group of obstructive STEMI ones.

Finally, they evaluated a score able to address and separate MINOCA from obstructive AMI patients hospitalized due to MI with ST segment elevation. The model showed that patients who scored more than 600 points had a 19% probability of MINOCA, and for patients scoring more than 650 points, the probability of MINOCA was 71%. The other end of the MINOCA probability scale was marginal for patients who scored less than 500 points (< .2%).

The strengths of this study are:

- First, the large population of the study. Indeed they evaluated more than 1 million patients from the Polish National Registry of Percutaneous Coronary Interventions (ORPKI). They selected a broad sample of STEMI underwent PCI and MINOCA with ST-segment elevation (more than 5600 ones). Respect to the current literature on MINOCA, this is a very large population though from a retrospective registry.

- They collected only ST-segment acute myocardial infarction. This is a specific group of patients, especially in the MINOCA, which is worth studying due to higher mortality, particularly intra-hospital.

- The idea of a model able to distinguish STEMI obstructive AMI vs STEMI MINOCA could be very useful in clinical practice due to the subsequent diagnostic and therapeutic implications.

- I appreciate the table 2 in which they showed the coronary angiography and procedural indices.

However, there are some limitations of this study. The major pitfalls are:

- MINOCA patients are a heterogeneous entity. The current literature considered as MINOCA only coronary ischemic causes of acute myocardial infarction without obstructive coronary arteries. In our clinical practice, we have to exclude non-cardiac causes of troponin surge but also cardiac conditions like tako-tsubo syndrome or acute myocarditis.

In this work, the MINOCA population is quite heterogeneous and seemed quite unselected. They had not well-established inclusion and exclusion criteria for MINOCA diagnosis. Moreover, what were the main causes of MINOCA? Did they use cardiac magnetic resonance or other secondary diagnostic tools to address the final MINOCA diagnosis, as the recent guidelines recommend?

- I think that the best clinical utility of the diagnostic model, created in this work, is to rule out the probability of MINOCA diagnosis. In fact, if the score is less than 500 points the probability of MINOCA is quite low < .2%. However, this model could not help the clinicians to avoid an urgent coronary angiography in patients with a suspected STEMI, even if the probability of obstructive CAD is low.

In the paper, the authors should explain more the clinical role of this predictive score (eg: in patients with high MINOCA probability, it’s useful to use more diagnostic tools, like left ventriculography during angiography or intravascular imaging, and to design a specific treatment in this population).

- It could be useful to create a predictive model with only pre-angiography variables, eg exclude P2Y12 inhibitors and add other variables like the presence of typical angina. This could be more useful for the clinicians as explained above.

Minor limitation:

- I suggest a more careful revision of the English language in the text

PONE-D-20-39776R1

ST-segment elevation myocardial infarction with non-obstructive coronary arteries: score derivation for prediction based on a large national registry

PLOS ONE

Dear Dr. Januszek,

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.

Please submit your revised manuscript by Jun 25 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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We look forward to receiving your revised manuscript.

Kind regards,

Raffaele Bugiardini, M.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: (No Response)

Reviewer #4: (No Response)

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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 #3: (No Response)

Reviewer #4: Partly

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

Reviewer #3: (No Response)

Reviewer #4: Yes

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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 #3: (No Response)

Reviewer #4: Yes

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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 #3: (No Response)

Reviewer #4: Yes

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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 #3: This work intended to design a score for predicting MINOCA among STEMI patients in the Polish national registry of PCIs. They analyzed 124,663 pPCI treated individuals and 5,695 individuals with STEMI and MINOCA. The results showed the significant difference between patients with MINOCA and those in the MI-CAD group based on the proposed MINOCA score.

1. Please make the table self-explained. The notation needs to be noted. For example, 120 [60 ÷ 330]. What does it mean in bracket?

2. Need to precisely provide the information how the score was constructed in method section.

3. Validation is required to comment on the model performance. It’s unclear how the authors evaluate the performance of the score. It seems that the same sample was used. If so, it would lead to inflated results for the performance. If not, detail information should be provided.

Reviewer #4: This study has used a large national registry of cardiac interventional procedures to evaluate the STEMI population undergoing urgent angiography in relation the presence or absence of coronary artery disease (CAD). They compared the clinical features of STEMI patients with CAD (MICAD) to STEMI patients without CAD (MINOCA) and performed a regression model to identify predictors of MINOCA patients in this cohort.

This study is one of few that has focused on the STEMI population, which is an important knowledge gap, considering data which highlights MINOCA patients do not have a negligible risk of adverse outcomes, thus raising concerns about prognosis and appropriate management in the STEMI MINOCA population.

The authors developed a predictive score from their regression model (a nomogram) which showed the following factors were associated with MINOCA: younger age, female gender, no history of prior CABG, no history of smoking, no arterial hypertension, presence of COPD, no treatment with

3rd generation P2Y12, no direct transport to hospital, Killip class I or II, no history of diabetes and greater body mass at admission.

The authors present a very large population in the study and the clinical focus area is important, however there are some concerns with the methodology and the subsequent interpretation of these findings which at large do not serve the improved understanding of the MINOCA population.

The key concerns is in relation to the MINOCA definition and diagnosis.

The 4th Universal Definition of AMI states that MINOCA is:

MI patients with no angiographic obstructive CAD (> 50% diameter stenosis in a major epicardial vessel) AND, MINOCA, like the diagnosis of MI, indicates that there is an ischaemic mechanism responsible for the myocyte injury (i.e., non-ischaemic causes such as myocarditis have been

excluded).

There are challenges of the use or misuse of the term MINOCA since the term should be exclusively reserved for those patients with confirmed MI and thus who have undertaken key investigations such as cardiac MRI.

There is very limited data on such patients and institutions have limited availability of additional diagnostic testing. As such the presented cohort in this study, like many others, is a heterogenous cohort of ‘suspected MINOCA’. This should be acknowledged upfront.

The authors should adopt this language of ‘suspected MINOCA’ in their manuscript and refer to the 4th Universal Definition in their limitations.

The term ‘predictive score for MINOCA’ or ‘MINOCA predictive score’ should not be used as this is misleading due to the heterogeneity in the cohort.

The introduction should also be clarified as other non-coronary conditions such as myocarditis do not cause MINOCA but rather mimic MINOCA.

The scientific reasoning provided for the need for such a predictive score requires careful consideration also. The authors state that ‘coronary angiography is only an exclusive tool’ and whilst there is no relevance of primary PCI in MINOCA, the diagnostic angiogram in STEMI is still relevant to identify other underlying conditions such as Takotsubo or spontaneous coronary artery dissection.

Such a tool being used to ‘triage’ patients away from urgent angiography inappropriately may cause harm.

The aim in the introduction should be re-worded, in particular the phrase ‘reach a diagnosis’ should be removed.

The results show that the MINOCA patients are significantly younger compared to MICAD.

Where subsequent analyses age-adjusted to reflect this important difference, in particular, for CVD risk factors which are known to increase with ag?

In relation to coronary angiography data, the authors state 71.57% of MINOCA had significant stenoses. This is confusing.

Since MINOCA patients, by definition, have non-obstructive CAD, I assume the authors refer to plaques less than 50%?

Can the authors please clarify this and confirm that the MINOCA and MICAD populations were defined based on the 50% stenosis threshold. Were these thresholds ascertained by the angiography reports and/or operating physicians?

The nomogram description (“in the form of a nomogram, that is, a graphical representation of the relative impact of each prognostic factor within the global model”) in the results should be moved to the Methods.

In the conclusion, the main aims should be carefully re-considered

“The main aim of this publication was to spark a discussion, and in the future, try to create a

scheme reducing the number of unnecessarily performed invasive coronary angiographies in

patients with acute STEMI.”

It may be difficult to find clinical acceptance for a need to reduce unnecessary angiograms in STEMI.

However, the authors make an excellent point that a potential use of such predictive algorithms is for pre-paring the operator for a possible MINOCA diagnosis and thus for additional testing. This is a key point that should be further emphasised as a major issue in current MINOCA management is the lack of additional diagnostic testing. The discussion of a possible MINOCA diagnosis would also help prepare patients who are often left with no understanding of their presentation and discharged without a diagnosis.

Thus, the use of predictive algorithms in MINOCA has a place but the derivation population must be defined appropriately, and the focus of the tool is used to improve management and communication in the health care process.

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Reviewer #3: No

Reviewer #4: No

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PONE-D-20-39776R2

ST-segment elevation myocardial infarction with non-obstructive coronary arteries: score derivation for prediction based on a large national registry

PLOS ONE

Dear Dr. Januszek,

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 following points: 

Please submit your revised manuscript by Aug 07 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Raffaele Bugiardini, M.D.

Academic Editor

PLOS ONE

Journal Requirements:

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.

Additional Editor Comments:

Though review articles are appropriately used as overview citations for broad scientific topics or ideas, most citations, especially those focusing on previously published concepts or results, should be of original research papers. The community also values the accurate assignment of credit and precedence for scientific discoveries. As so, please include in your revision references of larger studies, reporting contemporary cohorts in order to inform the audience on the heterogeneity of patients with MINOCA, specifically:

• Introduction, page  1, lines 2-3:  Circ Cardiovasc Qual Outcomes . 2017 Dec;10(12):e003443. doi: 10.1161/CIRCOUTCOMES.116.003443.
• Introduction page 1, lines 8-12: reference to this recently published original paper regarding the mechanism and etiologies of MINOCA should be added instead of the review paper-reference # 4: Circulation. 2021;143:624–640 doi: 10.1161/CIRCULATIONAHA.120.052008
• Introduction, page  2, lines 2-3:  Circ Cardiovasc Qual Outcomes . 2017 Dec;10(12):e003443. doi: 10.1161/CIRCOUTCOMES.116.003443 and Journal of the American Heart Association. 2020;9:e017235 doi: 10.1161/JAHA.120.017235
• Discussion in regard with the following statement” What is interesting, in studies on the use of DAPT in MINOCA patients, it is shown that therapy is not only of no benefit, but may be detrimental in this group of patients [20,21]”
  • Reference # 20 could be misleading for the audience and should be revised accordingly. The study was an underpowered single-center study and as such is not able to detect the possible benefit or harm of therapeutic regimes in the MINOCA population. References of larger robust studies should be reported instead see Circulation.  2017 Apr 18;135(16):1481-1489. doi: 10.1161/CIRCULATIONAHA.116.026336.
  • Reference # 21 refers to an abstract. The full manuscript recently published, should be reported instead: Heart. 2021 Jan 27;heartjnl-2020-318045. doi: 10.1136/heartjnl-2020-318045. PMID: 33504513. 
  • Additionally, with regard to the above-mentioned statement, it should be noted that, so far, possible harm associated with DAPT is mainly related to higher major bleeding rates, given also the higher incidence of MINOCA in women. In this regard the post-hoc analysis of the OASIS-7 trial (Heart. 2021 Jan 27;heartjnl-2020-318045. doi: 10.1136/heartjnl-2020-318045.) very nicely inform us about the possible harm related to intensified dosing strategy. Therefore, bleeding risk should be mentioned briefly.

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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 #3: All comments have been addressed

Reviewer #4: 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 #3: (No Response)

Reviewer #4: Yes

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

Reviewer #3: (No Response)

Reviewer #4: Yes

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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 #3: (No Response)

Reviewer #4: Yes

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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 #3: (No Response)

Reviewer #4: Yes

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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 #3: (No Response)

Reviewer #4: Dear Authors, comments have been addressed and incorporated into the manuscript.

Minor error on last page - MINOCA is spelt incorrectly "MINORC"

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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 #3: No

Reviewer #4: No

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ST-segment elevation myocardial infarction with non-obstructive coronary arteries: score derivation for prediction based on a large national registry

PONE-D-20-39776R3

Dear Dr. Januszek,

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,

Raffaele Bugiardini, M.D.

Academic Editor

PLOS ONE

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