PONE-D-20-03834

Associations of antithrombotic agent use with clinical outcomes in critically ill patients with detectable troponin I in the absence of acute coronary syndrome

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Reviewer #1: Re: PONE-D-20-03834

Associations of antithrombotic agent use with clinical outcomes in critically ill patients with detectable troponin I in the absence of acute coronary syndrome

The authors report a cohort of ~600 mixed medical/surgical ICU patients without primary cardiac diagnoses, the majority of who had sepsis and respiratory failure. They examined the characteristics and outcomes of those with and without detectable cardiac troponin I and the associations between use of antithrombotic therapies (including antiplatelet and anticoagulant drugs) with outcomes. As in prior studies, patients with detectable troponin levels were sicker and had worse outcomes. Patients who received chronic antithrombotic therapy had lower mortality, although patients who received new antithrombotics did not.

Specific comments:

Introduction:

1. The authors discuss Type 1 and type 2 MI at the end of the opening paragraph without defining these entities and emphasizing their differences. Then, at the beginning of the secondary paragraph, it is implied that obstructive CAD is the difference between type 1 and type 2 MI, which is not true per se. The authors should be consistent about these distinctions, and introduce the distinction between type 1 and 2 MI earlier in the manuscript.

Methods:

1. The authors state that the upper reference limit of their troponin I assay is 0.16, so why did they choose >0.1 as their cut-off to define an elevated troponin. This should be justified, and the authors should use consistent terminology throughout the manuscript (detectable versus higher versus elevated). In addition, the brand/name of the assay should be provided.

2. The authors define sepsis as an increase in the SOFA score—I presume this also requires the presence of known or suspected infection, and this should be stated explicitly.

3. The authors do not state how they specifically excluded ACS patients, and this should be clarified.

4. Propensity adjustment or inverse probability weighting would be a better method to account for the baseline differences between antithrombotic treatment groups

Results:

1. The section “Antithrombotic use during ICU stays in patients with troponin I elevation” is confusing in places. At times, all antithrombotics are considered together (chronic and new), and at other times these are separated. This should be stated more clearly.

2. The statement “The lengths of ICU stay and hospitalization did not differ between the elevated and normal troponin I groups; neither did the occurrence of in-hospital gastrointestinal tract bleeding or AKI; in-hospital 30-day, or 1-year mortality; or ventilator and dialysis dependence (Table 5)” seems out of place here—by context, I presume the authors mean that the outcomes did not differ as a function of antithrombotic use but this should be clarified.

3. The analyses should be clearly performed and stated comparing acute and chronic antithrombotic use.

4. The section “Subgroup analysis of patients with detectable troponin I” likewise seems to be poorly named, as this examined the effects of several subgroups analyses and the results are not stated very clearly. If the authors’ main finding is that patients with elevated troponin who were chronically on anticoagulants had lower mortality, but patients who were started on new antithrombotics did not then this should be clearly stated and appropriate analyses performed to demonstrate the point (and Figure 2 revised to show new vs. old antithrombotics).

5. The authors do not clearly report whether any of their patients subsequently underwent echocardiography, stress testing, coronary angiography or PCI and these data should be provided.

Discussion:

1. Throughout, the authors should state that the different exposures (high troponin, receipt of antithrombotics) were ASSOCIATED with higher/lower mortality in this observational study, not using words or phrases that imply causation.

2. In the second paragraph, the authors discuss at length potential causes of type 2 MI and non-MI troponin elevations, and this discussion should be shortened as it is not directly relevant to their main research hypothesis.

3. The authors don’t really explain why chronic antithrombotic use is associated with better outcomes—they suggest that it might be related to the underlying disease without proposing a plausible mechanism of benefit.

4. The authors subsequently discuss GI bleeding at length even though this was unexpectedly not seen in their patients who received antithrombotics—this discussion should be shortened.

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Reviewer #1: No

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Associations of antithrombotic agent use with clinical outcomes in critically ill patients with troponin I elevation in the absence of acute coronary syndrome

PONE-D-20-03834R1

Dear Dr. Huang,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

Corstiaan den Uil

Academic Editor

PLOS ONE

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