Association between the platelet‐lymphocyte ratio and short‐term mortality in patients with non‐ST‐segment elevation myocardial infarction

Abstract Background Previous studies have shown that inflammation plays an important role in atherosclerosis and cardiovascular disease. Platelet to lymphocyte ratio (PLR) has been reported as a novel inflammatory marker. However, it is not clear whether PLR is associated with short‐term all‐cause mortality in critically ill patients with non‐ST‐segment elevation myocardial infarction (NSTEMI). Methods The data for the study is from the Medical Information Mart for Intensive Care III database. The primary outcome in our study was 28‐day mortality. Kapan‐Meier curve, lowess smoother curve, and multivariate Cox regression models were used to determine whether the association between PLR and 28‐day mortality of critically ill patients with NSTEMI. Results A total of 1273 critically ill patients with NSTEMI were included in this analysis. Kapan‐Meier curve and lowess smoother curve show that high PLR is associated with an increased risk of 28‐day all‐cause mortality. The study population is divided into two groups according to the cut‐off value of PLR level. In the Cox model, high PLR levels (PLR≥195.8) were significantly associated with increased 28‐day mortality (HR 1.54; 95%CI 1.09–2.18, p = .013). In quartile analyses, the HR (95% CI) for the third (183 ≤ PLR < 306) and fourth quartile (PLR≥306) was 1.55 (1.05–2.29) and 1.61 (1.03–2.52), respectively, compared to the reference group(111 ≤ PLR < 183). In subgroup analyses, there is no interaction effect in most of the subgroups except for respiratory failure and vasopressor use. Conclusion High PLR is associated with an increased risk of short‐term mortality in critically ill patients with NSTEMI.


| INTRODUCTION
Heart disease is the leading reason for death worldwide, causing huge health and economic burden. 1,2 Previous studies have shown that inflammation plays an important role in atherosclerosis and cardiovascular disease. 3,4 Inflammation and oxidative stress can cause plaque rupture, which leads to cardiovascular events. 4,5 In recent years, platelet to lymphocyte ratio (PLR) has been reported as a novel inflammatory marker, which is related to the prognosis of many diseases, such as tumors, [6][7][8][9] rheumatic diseases, 10-12 diabetes 13,14 and cardiovascular diseases. [15][16][17] However, only a few studies have investigated PLR and the longterm prognosis of acute non-ST-segment elevation myocardial infarction (NSTEMI). 18,19 It is not clear whether PLR is associated with short-term all-cause mortality in critically ill patients with NSTEMI. Therefore, in this study, we investigated the correlation between PLR and the short-term outcome of critically ill patients with NSTEMI.

| Database and patient selection
All retrospective research data comes from Medical Information Mart for Intensive Care III (MIMIC database). The MIMIC database is a large, free-to-access database that more than 40 000 critical care patients. 20 The database is accessible to researchers who have completed a 'protecting human subjects' training. Data

| Data extraction
Since the database is based on a structured query language (SQL), we utilize the software pgAdmin to extract all research data in our research. Data extraction includes gender, age, ethnicity, heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP), blood oxygen saturation (Spo2). Extracted disease comorbidities include high blood pressure (HBP), diabetes mellitus (DM), chronic heart failure F I G U R E 1 Flow chart of patient selection (CHF), acute heart failure (AHF), respiratory failure, atrial fibrillation (Af), acute kidney injury (AKI), and chronic kidney disease (CKD). The extracted disease severity score is the Sequential Organ Failure Assessment (SOFA) score. We extracted laboratory tests, including white blood cells (WBC) count, platelet (PLT) count, neutrophil count, lymphocytes count, serum glucose, serum potassium, and serum creatinine (Scr). In addition, we also extracted some treatment measures including vasopressor use, dual antiplatelet therapy (DAPT), Abbreviations: AF, atrial fibrillation; AHF, acute heart failure; AKI, acute kidney injury (AKI); Spo2, blood oxygen saturation; CABG, coronary artery bypass grafting; CKD, chronic kidney disease; CHF, chronic heart failure; DAPT, dual antiplatelet therapy; DM, diabetes mellitus; DBP, diastolic blood pressure; HBP, high blood pressure; PCI, percutaneous coronary intervention; PLT, platelet count; PLR, platelet to lymphocyte ratio; RF, respiratory failure; SBP, systolic blood pressure; Scr, serum creatinine (Scr); SOFA, sequential organ failure assessment score; WBC, white blood cells count.
percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), and ventilator use. The primary endpoint was 28-day hospital mortality, which was defined as death 28 days after admission.

| Statistical analyses
Continuous variables are expressed as mean ± SD or median (IQR  and 28-day mortality of patients with NSTEMI, we draw the lowess smoother curve between PLR and 28-day mortality in additional material ( Figure S1). In this study, we found the 28-day mortality increased as PLR increased. In order to further clarify the relationship between PLR and the risk of 28-day mortality, we used a multivariate Cox model for analysis (

| Subgroup analysis
Subgroup analysis showed the correlation between PLR levels and 28-day mortality in patients ( promoting an inflammatory and immune response. 25,26 The lymphocyte count is affected by the level of cortisol. 27 The inflammatory response could cause the level of cortisol to rise, which may reduce lymphocyte count. 27 The higher level of PLR may indicate to a certain extent that the body's inflammatory Abbreviations: AF, atrial fibrillation; AHF, acute heart failure; AK, acute kidney injury; CKD, chronic kidney disease; CHF, chronic heart failure; DAPT, dual antiplatelet therapy; DM, diabetes mellitus; HBP, high blood pressure; PCI, percutaneous coronary intervention; SOFA, sequential organ failure assessment score.
response is more severe, which may be related to adverse clinical events.
To our knowledge, this is the first study to explore the relationship between PLR and short-term outcomes in critically ill patients with NSTEMI. PLR is easy to obtain and convenient for clinical use.
Admission PLR measurement may be used to stratify the prognosis risk of critically ill patients with NSTEMI and provide a reference for later treatment. Our study had several limitations. Although we found that high PLR is independently associated with adverse outcomes, the mechanism behind this association is unclear. Our hypothesis still needs further verification. Our study is a large sample study, but it is still a single-center retrospective study. We only collected the data of the patient on admission. The relationship between the dynamic changes of PLR and critically ill patients with NSTEMI cannot be analyzed.

| CONCLUSION
High PLR is associated with an increased risk of short-term mortality in critically ill patients with NSTEMI. Our findings need to be further validated by large prospective studies and longer follow-up time.

CONFLICTS OF INTEREST
The authors declare that they have no conflicts of interest.

DATA AVAILABILITY STATEMENT
These data were derived from the following resources available in the public domain: (https://physionet.org/content/mimiciii/1.4/).