Evaluation of the Use of Dual Antiplatelet Therapy beyond the First Year after Acute Coronary Syndrome

Round 1

Reviewer 1 Report

This article is a retrospective study on extended use of dual antiplatelet therapy (DAPT) in 770 patients with acute coronary syndrome (ACS). In merely 34.4% of patients who were potential candidates for an extended antiplatelet regime, DAPT was actually extended. Also, the PEGASUS criteria, also previously mentioned in the guidelines of the European Society of Cardiology (ESC), do not seem to be the determining factor in whether physicians choose to extend DAPT in ACS patients. Instead, criteria such as stent trombosis and extension of coronary artery disease are significantly associated with extended DAPT use. 

I believe this is a very relevant study, in a field where real-world data is scarce and lacking. Also, the study reflects the current daily practice, as many physicians are often reluctant to extend DAPT due to different reasons, despite the recommendations given by the ESC guidelines. The following points are some questions/suggestions which might improve the manuscript:

1. Table 1 and 2: How are 'Cardiac insufficiency' and 'ischemic cardiopathy' defined? Please elaborate in the text of the subscript of the tables. Also, 48% of patients have 'ischemic cardiopathy', but only 14.2% have had a previous PCI. Does the rest have a previous CABG of other types of documented coronary artery disease? It seems a bit disproportional, but I may have interpreted the meaning of 'ischemic cardiopathy' wrong.
   
   
2. I would recommend to mention the ESC 'risk criteria for extended treatment with a second antithrombotic agent' (Table 11 from the 2020 ESC Guidelines for the management of NSTE-ACS) in your discussion. These criteria seem to include some of the variables find in your study associated with the use of extended DAPT, rather than the PEGASUS criteria, which have been mentioned/recommended in the 2017 ESC guidelines on DAPT, but are not as prominent in the most recent 2020 guidelines. How do these new risk criteria effect your study and do you believe that these criteria are more suitable to identify those who should receive extended DAPT?
3.  Page 12, l. 314: typo: PRECISE-DAPT (not PRECISE-DART).

Author Response

This article is a retrospective study on extended use of dual antiplatelet therapy (DAPT) in 770 patients with acute coronary syndrome (ACS). In merely 34.4% of patients who were potential candidates for an extended antiplatelet regime, DAPT was actually extended. Also, the PEGASUS criteria, also previously mentioned in the guidelines of the European Society of Cardiology (ESC), do not seem to be the determining factor in whether physicians choose to extend DAPT in ACS patients. Instead, criteria such as stent trombosis and extension of coronary artery disease are significantly associated with extended DAPT use. 

I believe this is a very relevant study, in a field where real-world data is scarce and lacking. Also, the study reflects the current daily practice, as many physicians are often reluctant to extend DAPT due to different reasons, despite the recommendations given by the ESC guidelines. The following points are some questions/suggestions which might improve the manuscript:

1. Table 1 and 2: How are 'Cardiac insufficiency' and 'ischemic cardiopathy' defined? Please elaborate in the text of the subscript of the tables. Also, 48% of patients have 'ischemic cardiopathy', but only 14.2% have had a previous PCI. Does the rest have a previous CABG of other types of documented coronary artery disease? It seems a bit disproportional, but I may have interpreted the meaning of 'ischemic cardiopathy' wrong.

We appreciate the reviewer comment, and it is an opportunity to improve the understanding of the text. We have changed the term “cardiac insufficiency” to “heart failure”. It is defined as previous diagnosis of heart failure according to usual clinical practice guidelines definition. Also “ischemic cardiopathy” has been changed to “coronary artery disease”, as it is a more precise and more widely used term. It includes any possible clinical manifestation, from stable coronary artery disease to acute myocardial infarction. Stable coronary artery disease is frequently managed medically, also there is a not negligible percentage of ischemia without obstructive coronary disease either in chronic and acute coronary syndrome, both situations (together with CABG and conservative approaches) contribute to history of coronary artery disease without PCI. We also acknowledge that while previous PCI is a solid and objective antecedent, diagnosis of coronary artery disease may be laxer (as it frequently relies on subjective clinical assessment) and may therefore be overestimated.

The change in both terms have been implemented in tables 1 and 2. 

1. I would recommend to mention the ESC 'risk criteria for extended treatment with a second antithrombotic agent' (Table 11 from the 2020 ESC Guidelines for the management of NSTE-ACS) in your discussion. These criteria seem to include some of the variables find in your study associated with the use of extended DAPT, rather than the PEGASUS criteria, which have been mentioned/recommended in the 2017 ESC guidelines on DAPT, but are not as prominent in the most recent 2020 guidelines. How do these new risk criteria effect your study and do you believe that these criteria are more suitable to identify those who should receive extended DAPT?

We thank the reviewer for this pertinent comment. In order to include and discuss the question posed, we have added the following sentences to the discussion section (page 13):

“Recent ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation include a series of risk criteria for extended treatment with a second antithrombotic agent based on the combined evidence of clinical trials and registries addressing this topic [3]. Stent thrombosis, recurrent myocardial infarction and multivessel coronary disease are the main variables independently associated with extended DAPT in our study, and all of them are included in the aforementioned risk criteria. These variables easily identify a high-risk profile, so it is not surprising that they are the most used in clinical daily practice in our study. However, this approach excludes other variables included both in the PEGASUS criteria and in the ESC guidelines, that also pose a higher risk. Therefore, the decision on extended DAPT in clinical practice seem to rely on some important variables but ignore other relevant factors, and the result is an underuse of this strategy.”

1.  Page 12, l. 314: typo: PRECISE-DAPT (not PRECISE-DART).

This typo has been corrected.

Reviewer 2 Report

I read with interest the paper by Dr Bonadad and colleagues. In their work the authors analyzed factors associated with the extension of dual antiplatelet therapy beyond one year in a real word cohort of patients ( n=1967) discharged after ACS. The subject is of interest as previously many studies highlighted a noteworthy discrepancy between current guidelines recommendations and clinical practice.  In this light, Authors’ findings contribute to the existing evidence by showing that neither PEGASUS criteria neither patients’ bleeding risk were independently associated with DAPT prosecution after multivariate adjustment; On the other hand, the prescription of Clopidogrel at discharge was found an independent predictor of DAPT extension as compared to potent P2Y12 inhibitors.  This is kind of unusual as clopidogrel should be deserved for high bleeding risk patients. Therefore, the authors' findings overall stress the lack of calibration between physicians’ perceived risk and actual benefit from drugs prescription.

 

Specific comments.

Table 2 is cut in its right margin in the provided PDF, therefore I do not see the significance of univariate analysis.

The inclusion of 1967 ACS patients among 10 hospitals over a 2-year period appears somewhat low. Were there any other exclusion criteria except from the need for oral anticoagulation that should be stated?

Further, among exclusion criteria, authors enlist patients who “developed any thrombotic, hemorrhagic, or trans-109 fusion-related events during the first year”; however, in table 1 there is 1.1% of patients who experienced reinfarction and major bleeding during hospitalization. Please clarify.

Please provide an appropriate definition for “cardiac insufficiency”

The authors state that:

 “Ultimately, a total of  770 patients (39.1%) were estimated to be candidates for extending DAPT beyond 1 year based on the presence of a PEGASUS criterion and absence of high bleeding risk. DAPT  was extended in 34.4% of these potential candidates”.

And discussion line 305: Overall, 770 patients (39.1%) met this definition, of which only 34.4% 305 received extended therapy, demonstrating that this strategy is clearly underused” In this sentences, it is like 34.4% out of 39.1% of patients had DAPT extension.  However, in figure 2 and from the results presentation it appears that 34.4% of the whole sample size had DAPT extension. Please clarify or rephrase the sentence.

 

Discussion line 300-301: we found that 32.2% of patients received DAPT extended beyond 1 year. Please correct as I suppose these should be 34,4%.

 

Line 314: PRECISE DART-> PRECISE DAPT.

Author Response

I read with interest the paper by Dr Bonadad and colleagues. In their work the authors analyzed factors associated with the extension of dual antiplatelet therapy beyond one year in a real word cohort of patients ( n=1967) discharged after ACS. The subject is of interest as previously many studies highlighted a noteworthy discrepancy between current guidelines recommendations and clinical practice.  In this light, Authors’ findings contribute to the existing evidence by showing that neither PEGASUS criteria neither patients’ bleeding risk were independently associated with DAPT prosecution after multivariate adjustment; On the other hand, the prescription of Clopidogrel at discharge was found an independent predictor of DAPT extension as compared to potent P2Y12 inhibitors.  This is kind of unusual as clopidogrel should be deserved for high bleeding risk patients. Therefore, the authors' findings overall stress the lack of calibration between physicians’ perceived risk and actual benefit from drugs prescription.

Specific comments.

Table 2 is cut in its right margin in the provided PDF, therefore I do not see the significance of univariate analysis.

We have changed the table format to solve this problem

The inclusion of 1967 ACS patients among 10 hospitals over a 2-year period appears somewhat low. Were there any other exclusion criteria except from the need for oral anticoagulation that should be stated?

We appreciate the reviewer comment. First, we must highlight that the registry did not include all ACS patients. Inclusion criteria included PCI, therefore, conservatively managed patients (either initial or non-revascularizable), myocardial infarction with non-obstructive coronary arteries and CABG patients were not included. Apart from oral anticoagulation, the occurrence of any ischemic or hemorrhagic events during the first year after the index events were also exclusion criteria. All these criteria are included in the study population subsection of methods.

Further, among exclusion criteria, authors enlist patients who “developed any thrombotic, hemorrhagic, or trans-109 fusion-related events during the first year”; however, in table 1 there is 1.1% of patients who experienced reinfarction and major bleeding during hospitalization. Please clarify.

We thank the reviewer for the opportunity to clarify this point. The mentioned exclusion criterion refers to any event after discharge. Reinfarction during index admission was not an exclusion criterion, because DAPT must be equally continued. If a bleeding event occurred during index admission the patient could be included providing that was discharged on DAPT.

The corresponding paragraph in methods section has been modified subsequently:

“Patients with an indication for oral anticoagulation at discharge or if this indication emerged during the first year or who developed any thrombotic, hemorrhagic, or transfusion-related events during the first year after discharge were excluded.”

Please provide an appropriate definition for “cardiac insufficiency”

We acknowledge that this terminology is confusing. We have changed the term to “heart failure”, which is more accurate and identifiable.

The authors state that:

 “Ultimately, a total of  770 patients (39.1%) were estimated to be candidates for extending DAPT beyond 1 year based on the presence of a PEGASUS criterion and absence of high bleeding risk. DAPT  was extended in 34.4% of these potential candidates”.

And discussion line 305: Overall, 770 patients (39.1%) met this definition, of which only 34.4% 305 received extended therapy, demonstrating that this strategy is clearly underused” In this sentences, it is like 34.4% out of 39.1% of patients had DAPT extension.  However, in figure 2 and from the results presentation it appears that 34.4% of the whole sample size had DAPT extension. Please clarify or rephrase the sentence.

Discussion line 300-301: we found that 32.2% of patients received DAPT extended beyond 1 year. Please correct as I suppose these should be 34,4%.

We thank the reviewer this appreciation. We will try to clarify:

• In 32.2% of the whole sample DAPT was extended beyond 1 year. It is stated in section 3.1 DAPT duration
• In the subgroup defined as candidates for prolonged DAPT based on PEGASUS criterion and absence of bleeding risk, the percentage of DAPT prolongation was 34.4%

Both percentages are quite similar, which may be confusing. Moreover, there is a mistake in Figure 2, as it should express the percentage of the global sample (32.2%). It has been corrected in the new version of the manuscript. Also, the reference of Figure 2 has been moved to the “3.1 DAPT duration” section.

Discussion percentages are therefore correct.

Line 314: PRECISE DART-> PRECISE DAPT.

This typo has been corrected.

Reviewer 3 Report

In this manuscript Bonanad et al. present the proportion of patients with prolonged DAPT beyond 1 year after ACS from a cohort of 1967 consecutive ACS patients and analysed the independent predictors of prolongation. 

This retrospective observational study conducted in 10 hospitals in Spain.The study is meticulously performed in terms of the thorough statistical analyses. The main limitation of the study, namely its single-center observational design, is adequately addressed in the limitations section.

Major Points

The design of this study seems problematic. In my opinion, it would be of great interest to compare the incidence of major adverse cardiovascular events in patients with prolonged DAPT versus all other patients without prolonged DAPT but with indication for prolonged dual antiplatelet therapy using multivariate analysis. 

The authors state that the aim of their study was to determine the impact of the PEGASUS criteria on the decision to prolong DAPT. However, 30% of patients at discharge were treated with clopidogrel and 11% with prasugrel. Hence, the PEGASUS criteria for prolonged DAPT could not be established in this type of setting. The PEGASUS criteria can be applied only to patients receiving ASA and ticagrelol as DAPT.  The authors report that clopidogrel use was significantly associated with the use of prolonged DAPT in patients that met at least one PEGASUS criterion which is not logical, since these criteria do not apply to this population.

In addition, the authors evaluated the complexity of CAD using a score that is not validated. According to recent guidelines of NSTEMI, the complexity of CAD (which is indicative of high thrombotic risk) should be evaluated using well-known and validated scores such as the SYNTAX-score.

Minor Comments

1) In the abstract, the objectives of this manuscript are not clearly presented.

2)<<extension of coronary artery disease>>. Please modify to CAD severity/complexity

3) Why the authors chose the limit of ≥70% and not ≥60% as significant for severe CAD?

4) <<These findings led clinical practice guidelines to recommend implementing the strategy of prolonging DAPT in patients with high ischemic risk and without high bleeding risk>> .  This sentence needs significant changes.

5) Table 1. The authors report Cardiac insufficiency. Do they mean Heart Failure ?

Please change ADA to LAD

Ref: Farooq V, van Klaveren D, Steyerberg EW, Meliga E, Vergouwe Y, Chieffo A, Kappetein AP, Colombo A, Holmes DR Jr, Mack M, Feldman T, Morice MC, Ståhle E, Onuma Y, Morel MA, Garcia-Garcia HM, van Es GA, Dawkins KD, Mohr FW, Serruys PW. Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and validation of SYNTAX score II. Lancet. 2013 Feb 23;381(9867):639-50. doi: 10.1016/S0140-6736(13)60108-7. PMID: 23439103.

 

Author Response

In this manuscript Bonanad et al. present the proportion of patients with prolonged DAPT beyond 1 year after ACS from a cohort of 1967 consecutive ACS patients and analysed the independent predictors of prolongation. 

This retrospective observational study conducted in 10 hospitals in Spain.The study is meticulously performed in terms of the thorough statistical analyses. The main limitation of the study, namely its single-center observational design, is adequately addressed in the limitations section.

Major Points

The design of this study seems problematic. In my opinion, it would be of great interest to compare the incidence of major adverse cardiovascular events in patients with prolonged DAPT versus all other patients without prolonged DAPT but with indication for prolonged dual antiplatelet therapy using multivariate analysis. 

We agree with the reviewer that it would be of great interest. However, the study lacks statistical power to draw solid conclusions and it would be subjected to relevant biases. Furthermore, our aim was to describe the “picture” of real-life prescription of prolonged DAPT and to analyze the determinants of this decision, the clinical benefit of this strategy largely relies on clinical trials and observational registries may add limited evidence.

We have added the following sentence in the limitations paragraph to acknowledge this issue:

“Finally, the study lacks statistical power to compare clinical events between treatment strategies (i.e., 12 months vs extended DAPT)”

The authors state that the aim of their study was to determine the impact of the PEGASUS criteria on the decision to prolong DAPT. However, 30% of patients at discharge were treated with clopidogrel and 11% with prasugrel. Hence, the PEGASUS criteria for prolonged DAPT could not be established in this type of setting. The PEGASUS criteria can be applied only to patients receiving ASA and ticagrelol as DAPT.  The authors report that clopidogrel use was significantly associated with the use of prolonged DAPT in patients that met at least one PEGASUS criterion which is not logical, since these criteria do not apply to this population.

We find the reviewer`s comment pertinent and relevant, and we will try to clarify this point. PEGASUS trial is one of the main pivotal trials supporting the strategy of DAPT prolongation, and it included patients with at least one of a list of limited criteria, which are solid and easily identifiable. Our aim was to evaluate the proportion of patients with DAPT extension and to identify the variables independently associated with this strategy. Within this broad objective, we believed that it was interesting to test the role of this PEGASUS criteria, given the high impact of this clinical trial on the scientific evidence. It is true that ESC guidelines recommend considering DAPT prolongation in patients with a high risk of ischaemic events and propose a series of criteria to support this decision (ESC guidelines on NSTEMI, table 11) which includes but is not limited to the PEGASUS criteria, and our study have analyzed most of these variables.

In order to reflect this difference between ESC and PEGASUS criteria, we have included the following sentences in the discussion section:

“Recent ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation include a series of risk criteria for extended treatment with a second antithrombotic agent based on the combined evi-dence of clinical trials and registries addressing this topic [3]. Stent thrombosis, recur-rent myocardial infarction and multivessel coronary disease are the main variables in-dependently associated with extended DAPT in our study, and all of them are includ-ed in the aforementioned risk criteria. These variables easily identify a high-risk pro-file, so it is not surprising that they are the most used in clinical daily practice in our study. However, this approach excludes other variables included both in the PEGASUS criteria and in the ESC guidelines, that also pose a higher risk. Therefore, the decision on extended DAPT in clinical practice seem to rely on some important variables but ignore other relevant factors, and the result is an underuse of this strategy.”

On the other hand, PEGASUS trial did not exclude patients previously treated with a P2Y12 inhibitor different from ticagrelor, and there are no different recommendations for DAPT prolongation criteria based on the second antiplatelet used. However, we acknowledge that PEGASUS criteria were not tested to clopidogrel prolongation. Therefore, we have performed an additional analysis of the extended DAPT predictors in the subgroup of patients treated with ticagrelor, with similar results regarding to PEGASUS criteria. We have added the following paragraphs:

• In results:

“Finally, an additional multivariate analysis was performed to identify variables associated with extended DAPT in the subgroup of patients treated with ticagrelor. Previous PCI, previous coronary artery disease, type of acute coronary syndrome, cor-onary artery disease complexity and reinfarction during index admission, were inde-pendently associated with prolongation of DAPT. Although univariate analysis found that the presence of at least 1 PEGASUS criterion was significantly associated with ex-tending DAPT, this was not confirmed in the multivariate model.”

• In discussion:

“The results of our study show an association between the presence of a PEGASUS clinical trial criterion and the prolongation of DAPT. However, this finding is not in-dependently confirmed in the multivariate analysis. Similar findings were obtained analyzing only the subgroup of patients receiving ticagrelor.”

Finally, the results of our study found that clopidogrel use was independently associated with DAPT extension in the whole sample, not only in patients with at least one PEGASUS criterion, as we state in the manuscript:

“In the multivariate analysis with logistic regression, the variables that showed statistically significant associations with extending DAPT were: a history of PCI, stent thrombosis, the extension of coronary disease (a discrete variable constructed by assigning 1 point for each of the following: involvement of the left coronary left main and/or proximal anterior descending coronary artery and/or multivessel disease, for a score of 0 to 3), reinfarction during index admission, and clopidogrel use (versus ticagrelor or prasugrel) (Table 3).”

In addition, the authors evaluated the complexity of CAD using a score that is not validated. According to recent guidelines of NSTEMI, the complexity of CAD (which is indicative of high thrombotic risk) should be evaluated using well-known and validated scores such as the SYNTAX-score.

We agree with the reviewer that the score used is not validated in other cohorts. However, NSTEMI guidelines include among the risk criteria for extended treatment with a second antithrombotic agent (table 11) literally “any multivessel CAD”. Additionally, technical aspects suggested in this criteria list include history of complex revascularization (left main, bifurcation, chronic total occlusion, and last patent vessel. Guidelines do not recommend any specific score for this purpose. In fact, PEGASUS and DAPT trial do not include SYNTAX score or other similar validated score as inclusion criteria or to perform any analysis. SYNTAX score is recommended in NSTEMI guidelines to help in the choice of the revascularization modality, as it was the aim of the SYNTAX trial.

Returning to the score used in our study, we think that is an easy and reproducible way to identify and semiquantify multivessel disease. It does not pretend to be an exhaustive description of the coronary complexity, neither guide any therapeutic decision. To clarify this point, we have added the following sentences to the discussion:

“The complexity of the coronary artery disease is recognized as a high-risk criterion of ischemic events, and it may support DAPT extension [3]. We have used a semiquantitative scale to represent this coronary complexity that is easy and reproducible, however, it is not a validated score for any clinical purpose.”

Minor Comments

• In the abstract, the objectives of this manuscript are not clearly presented.

We have rewritten the first part of the abstract to include the following sentence:

The complexity of the coronary artery disease is recognized as a high-risk criterion of ischemic events, and it may support DAPT extension [3]. We have used a semiquantitative scale to represent this coronary complexity, that is easy and reproducible, however, it is not a validated score for any clinical purpose.

2)<<extension of coronary artery disease>>. Please modify to CAD severity/complexity

It has been changed in all the manuscript

• Why the authors chose the limit of ≥70% and not ≥60% as significant for severe CAD?

We agree that angiographic threshold for severe stenosis may vary between different recommendations. However, 70% is a validated and commonly used threshold in our environment. We have to include also physiological assessment criteria in the definition in our manuscript:

“obstructive coronary artery disease (defined as stenosis ≥ 50% of the left coronary ar-tery and ≥ 70% of any other artery, or invasive evidence of ischemia)”

(Arbab-Zadeh A, Fuster V. The Risk Continuum of Atherosclerosis and its Implications for Defining CHD by Coronary Angiography. Journal of the American College of Cardiology. 2016;68(22):2467-2478. doi:10.1016/j.jacc.2016.08.069)

• <<These findings led clinical practice guidelines to recommend implementing the strategy of prolonging DAPT in patients with high ischemic risk and without high bleeding risk>> .  This sentence needs significant changes.

We have rephrased to:

“Clinical practice guidelines recommend extended DAPT in patients with high ischemic risk and without high bleeding risk based on these evidence”

• Table 1. The authors report Cardiac insufficiency. Do they mean Heart Failure ?

The correct term is heart failure and is has been changed accordingly

Please change ADA to LAD

It has been changed.

Round 2

Reviewer 3 Report

The authors have revised the manuscript and answered most of the questions raised by the reviewers. Still, I have one major comment that needs to be properly answered.

Major Comment.

The authors agreed that the score used to assess coronary complexity with a simplistic grading system is not validated. They also state that current guidelines do not recommend any specific score for CAD complexity assessment. Indeed, current guidelines do not recommend any specific score for the assessment of CAD complexity. However, guidelines specifically recommend that patients with high thrombotic risk are those with high CAD complexity AND at least one criterion from risk enhancers or Technical aspects. Clearly, the authors should have assessed CAD complexity using one of the many validated scores worldwide and not a score created with simplistic rules. For example, any multivessel disease might not be at the same time of high coronary complexity. That's why guidelines recommend extended DAPT In patients with high CAD complexity AND one risk enhancer (i.e multivessel disease).

The SYNTAX score algorithm was developed in order to stratify CAD complexity taking into account anatomic risk factors such as the number of lesions, lesion location, if a lesion is occlusive and other adverse lesion characteristics (bi/trifurcations, aorto-ostial stenosis, tortuosity, lesion length >20mm, calcification, thrombus, diffuse disease). It is one of the most well-known and validated scores in interventional cardiology worldwide. It is easy to understand that the simplistic score proposed by the authors does not reflect the complexity of CAD.   I suggest the authors to erase coronary artery disease complexity (and this oversimplified score) from their manuscript. Otherwise, the authors should calculate CAD complexity using a verified score such as the SYNTAX score.   Minor points 1) In the abstract section l. 42 a sentence seems to be missing. 2) In the conclusions section I would delete lines 393-395. << (ischemic risk criteria...extended DAPT).   

Author Response

We would like to thank the reviewer for the positive, thoughtful and constructive comments and suggestions.

As requested by the Editor, a list of responses is described below including the changes made in accordance with the reviewers’ suggestions.

A revised version of the manuscript with tracked changes has been uploaded.

Major Comment.

The authors agreed that the score used to assess coronary complexity with a simplistic grading system is not validated. They also state that current guidelines do not recommend any specific score for CAD complexity assessment. Indeed, current guidelines do not recommend any specific score for the assessment of CAD complexity. However, guidelines specifically recommend that patients with high thrombotic risk are those with high CAD complexity AND at least one criterion from risk enhancers or Technical aspects. Clearly, the authors should have assessed CAD complexity using one of the many validated scores worldwide and not a score created with simplistic rules. For example, any multivessel disease might not be at the same time of high coronary complexity. That's why guidelines recommend extended DAPT In patients with high CAD complexity AND one risk enhancer (i.e multivessel disease).

The SYNTAX score algorithm was developed in order to stratify CAD complexity taking into account anatomic risk factors such as the number of lesions, lesion location, if a lesion is occlusive and other adverse lesion characteristics (bi/trifurcations, aorto-ostial stenosis, tortuosity, lesion length >20mm, calcification, thrombus, diffuse disease). It is one of the most well-known and validated scores in interventional cardiology worldwide. It is easy to understand that the simplistic score proposed by the authors does not reflect the complexity of CAD.   I suggest the authors to erase coronary artery disease complexity (and this oversimplified score) from their manuscript. Otherwise, the authors should calculate CAD complexity using a verified score such as the SYNTAX score.  

Thank you for your comment since we find it highly pertinent. Therefore we have omitted all reference to the complexity of CAD, as it may be confounding. We have included in the analysis independently the following variables related to coronary stenosis: left main, proximal LAD and multivessel disease. Proximal LAD and multivessel disease were independently associated with DAPT prolongation. The whole manuscript has been changed accordingly.

Furthermore, we have added the following sentence in the limitations paragraph:

“The use of a validated score to assess coronary complexity may have provided additional useful information.”

 

 Minor points 

1) In the abstract section l. 42 a sentence seems to be missing. 

The following sentence was deleted by mistake, and it has been included again:

“The aim of this study was to identify variables associated with DAPT prolongation in a cohort of 1,967 consecutive patients discharged after ACS without thrombotic or hemorrhagic events dur-ing the following year”

 

2) In the conclusions section I would delete lines 393-395. << (ischemic risk criteria...extended DAPT).

It has been deleted