Bećirović E, Bećirović M, Šegalo S, Bećirović A, Hadžić S, Ljuca K, Papić E, Ferhatbegović L, Ejubović M, Jagodić Ejubović A, Kovčić A, Šljivo A, Begagić E. Hemogram-derived ratios as prognostic markers for major adverse cardiovascular events in patients with non-ST-segment elevation myocardial infarction. World J Methodol 2025; 15(2): 98143 [DOI: 10.5662/wjm.v15.i2.98143]
Corresponding Author of This Article
Emir Begagić, MD, Academic Research, Department of General Medicine, University of Zenica, School of Medicine, Zenica 72000, Bosnia and Herzegovina. begagicem@gmail.com
Research Domain of This Article
Critical Care Medicine
Article-Type of This Article
Prospective Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Emir Bećirović, Department of Intensive Care, University Clinical Center Tuzla, Tuzla 75000, Bosnia and Herzegovina
Minela Bećirović, Department of Nephrology, University Clinical Center Tuzla, Tuzla 75000, Bosnia and Herzegovina
Sabina Šegalo, Emsel Papić, Department of Laboratory Technologies, Faculty of Health Sciences, University of Sarajevo, Sarajevo 71000, Bosnia and Herzegovina
Amir Bećirović, Semir Hadžić, Department of Endocrinology, University Clinical Center Tuzla, Tuzla 75000, Bosnia and Herzegovina
Kenana Ljuca, School of Medicine, University of Tuzla, Tuzla 75000, Bosnia and Herzegovina
Lamija Ferhatbegović, Department for Internal Diseases and Hemodialysis, Canton Hospital Zenica, Zenica 72000, Bosnia and Herzegovina
Malik Ejubović, Amira Jagodić Ejubović, Department of Internal Medicine, Canton Hospital Zenica, Zenica 72000, Bosnia and Herzegovina
Amila Kovčić, Department of Radiotherapy, University Clinical Center Tuzla, Tuzla 75000, Bosnia and Herzegovina
Armin Šljivo, Department of Cardiology, University Clinical Center Sarajevo, Sarajevo 72000, Bosnia and Herzegovina
Emir Begagić, Department of General Medicine, University of Zenica, School of Medicine, Zenica 72000, Bosnia and Herzegovina
Co-first authors: Emir Bećirović and Minela Bećirović.
Author contributions: Bećirović E and Bećirović M designed the research study; Bećirovic A, Hadžić S, and Ljuca K performed the research; Šegalo S and Papić E supervised the research; Ferhatbegović L, Ejubović M and Ejubović AJ wrote the manuscript; Kovčić A, Šljivo A and Begagić E analyzed the data. All authors have read and approved the final manuscript.
Institutional review board statement: This study was approved by the Ethics Committee at University Clinical Centre Tuzla, Bosnia and Herzegovina, No: 02-09/2-97-21.
Clinical trial registration statement: No application for registration was made for this study.
Informed consent statement: All study participants, or their legal guardians, provided written consent prior to study enrolment.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: There is no additional data available.
CONSORT 2010 statement: The authors have read the CONSORT 2010 Statement, and the manuscript was prepared and revised according to the CONSORT 2010 Statement.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Emir Begagić, MD, Academic Research, Department of General Medicine, University of Zenica, School of Medicine, Zenica 72000, Bosnia and Herzegovina. begagicem@gmail.com
Received: June 18, 2024 Revised: September 29, 2024 Accepted: October 20, 2024 Published online: June 20, 2025 Processing time: 161 Days and 13.7 Hours
Abstract
BACKGROUND
Non-ST segment elevation myocardial infarction (NSTEMI) poses significant challenges in clinical management due to its diverse outcomes. Understanding the prognostic role of hematological parameters and derived ratios in NSTEMI patients could aid in risk stratification and improve patient care.
AIM
To evaluate the predictive value of hemogram-derived ratios for major adverse cardiovascular events (MACE) in NSTEMI patients, potentially improving clinical outcomes.
METHODS
A prospective, observational cohort study was conducted in 2021 at the Internal Medicine Clinic of the University Hospital in Tuzla, Bosnia and Herzegovina. The study included 170 patients with NSTEMI, who were divided into a group with MACE and a control group without MACE. Furthermore, the MACE group was subdivided into lethal and non-lethal groups for prognostic analysis. Alongside hematological parameters, an additional 13 hematological-derived ratios (HDRs) were monitored, and their prognostic role was investigated.
RESULTS
Hematological parameters did not significantly differ between non-ST segment elevation myocardial infarction (NSTEMI) patients with MACE and a control group at T1 and T2. However, significant disparities emerged in HDRs among NSTEMI patients with lethal and non-lethal outcomes post-MACE. Notably, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were elevated in lethal outcomes. Furthermore, C-reactive protein-to-lymphocyte ratio (CRP/Ly) at T1 (> 4.737) demonstrated predictive value [odds ratio (OR): 3.690, P = 0.024]. Both NLR at T1 (> 4.076) and T2 (> 4.667) emerged as significant predictors, with NLR at T2 exhibiting the highest diagnostic performance, as indicated by an area under the curve of 0.811 (95%CI: 0.727-0.859) and OR of 4.915 (95%CI: 1.917-12.602, P = 0.001), emphasizing its important role as a prognostic marker.
CONCLUSION
This study highlights the significant prognostic value of hemogram-derived indexes in predicting MACE among NSTEMI patients. During follow-up, NLR, PLR, and CRP/Ly offer important insights into the inflammatory processes underlying cardiovascular events.
Core Tip: This study underscores the significant role of hematological-derived ratios in predicting major adverse cardiovascular events (MACE) among NSTEMI patients. Elevated neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were associated with higher mortality rates post-MACE, with NLR at follow-up showing the highest predictive accuracy (area under the curve of 0.811). These findings suggest that monitoring NLR, PLR, and C-reactive protein-to-lymphocyte ratio (CRP/Ly) can offer valuable insights into the inflammatory mechanisms at play in cardiovascular risk, aiding in early intervention and improving patient outcomes.
Citation: Bećirović E, Bećirović M, Šegalo S, Bećirović A, Hadžić S, Ljuca K, Papić E, Ferhatbegović L, Ejubović M, Jagodić Ejubović A, Kovčić A, Šljivo A, Begagić E. Hemogram-derived ratios as prognostic markers for major adverse cardiovascular events in patients with non-ST-segment elevation myocardial infarction. World J Methodol 2025; 15(2): 98143
Non-ST-segment elevation myocardial infarction (NSTEMI) is a significant and growing subset of acute coronary syndromes (ACS) characterized by partial coronary artery blockage[1,2]. Recent trends show an increase in NSTEMI cases compared to STEMI, with notable variations across populations and demographics[3]. NSTEMI prevalence within ACS ranges from 14.2%[4] to 30.0%[5]. Despite being less dramatic in its presentation, NSTEMI typically has a worse prognosis than STEMI, with increased rates of severe myocardial infarction, stroke, cardiovascular death, and overall mortality[1].
Managing NSTEMI requires early diagnosis and intervention to mitigate adverse outcomes[6]. The rise in percutaneous coronary intervention underscores evolving strategies to improve clinical outcomes for NSTEMI patients[7]. However, there is a critical need for reliable prognostic markers to refine risk stratification and guide therapeutic decisions.
Hematologic-derived ratios (HDR) have emerged as promising prognostic tools in NSTEMI[8]. Their importance is also reflected in the assessment of inflammation. Coronary diseases are accompanied by inflammation due to the complex interplay of immune processes. These processes contribute to significant changes in the hematopoietic system, directly reflected in the absolute and relative number of cells. Usually, these are leukocytes such as neutrophils, lymphocytes, and monocytes. This is precisely one of the reasons for the increasing need for detailed research on HDRs in coronary disease to justify their use in daily practice, as they can help clinicians understand the pathophysiologic mechanism of disease. Elevated levels of these indices correlate with worse outcomes, including increased mortality, in-hospital complications, and long-term adverse cardiovascular events[9-12].
Most studies have used traditional HDR such as neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), and platelet/lymphocyte ratio (PLR)[13-16]. In addition to hematological parameters, inflammatory parameters such as C-reactive protein (CRP) values have been used to calculate HDR[17]. Determining CRP as an acute phase reactant is important for evaluating patients with an inflammatory response in ACS, monitoring disease progression, and patient stratification. CRP levels have been observed to correlate with higher mortality and myocardial damage[18]. However, caution should be exercised when interpreting the results, as these patients often have an atherosclerotic mass and underlying inflammation. Given the risk of individual variations in CRP levels and certain hematologic parameters in cardiovascular events, several studies have investigated the potential of the new HDR understudied in NSTEMI patients[19]. Evaluating their predictive accuracy for major adverse cardiovascular events (MACE) in NSTEMI patients could significantly enhance clinical decision-making and patient management in resource-limited settings. This study aims to evaluate the predictive value of hemogram-derived ratios for MACE in NSTEMI patients, potentially improving clinical outcomes.
MATERIALS AND METHODS
Study design and patients
A prospective, observational cohort study was conducted in the first half of 2021 at the Internal Medicine Clinic of the University Hospital in Tuzla, Bosnia and Herzegovina. The study included 170 hospitalized patients over 18 years old with newly diagnosed NSTEMI and without previous conventional therapy treatment with clopidogrel. All patients with (1) Prior clopidogrel treatment for any indication; (2) STEMI; (3) Stable coronary artery disease; (4) Previous NSTEMI; (5) Renal dysfunction; and (6) Hematologic diseases were excluded from this study. The study was approved by the Ethical Committee of the University Clinical Centre Tuzla, Bosnia and Herzegovina (No: 02-09/2-97-21). The patients were divided into two groups based on the occurrence of MACE following NSTEMI, and further analysis subdivided the MACE group into those with fatal and non-fatal outcomes.
All NSTEMI patients underwent a follow-up for six months after admission to assess MACEs. MACE included patients who experienced myocardial infarction, cardiovascular death, revascularization such as angioplasty or CABG, and hospitalization due to unstable angina or heart failure. The definitions for clinical outcomes (MACE) were according to the international classification of diseases. Clinical follow-up was performed by telephone or through a patient's examination.
Methods
Venous blood samples were taken from all patients at two-time points: On admission (T1) and after 24 hours (T2). Blood samples for the determination of complete blood count parameters were collected in test tubes containing K2EDTA (dipotassium ethylenediaminetetraacetic acid) as an anticoagulant and analyzed using a Sysmex XN-1000 automated haematology analyzer (Sysmex Corporation, Japan). For white blood cells, optical detection of semiconductor lasers and flow cytometry were used, while for red blood cells and platelet counting, sheath flow direct current detection was used. CRP quantification was performed using the immunoturbidimetric method using a Beckman Coulter DxC 700 AU biochemical analyzer (Beckman Coulter Diagnostic, Switzerland). Both analyzers are equipped with original reagents, controls, and calibrations, and were operated according to the manufacturer's instructions.
We calculated 13 HDR based on laboratory test results, following the methodology in Segalo et al[12]. The NLR was calculated as neutrophils divided by lymphocytes. The Derived NLR was computed as neutrophils divided by the difference between total white blood cells and neutrophils. The neutrophil-to-platelet ratio was determined by neutrophils divided by platelets, and the neutrophil-to-lymphocyte platelet ratio (NLPR) by neutrophils divided by the product of lymphocytes and platelets. The PLR was calculated as platelets divided by lymphocytes. The monocyte to neutrophil ratio (MNR) was calculated by dividing monocytes by neutrophils, and the MLR by dividing monocytes by lymphocytes. The lymphocyte to monocyte ratio was calculated as lymphocytes divided by monocytes. The lymphocyte to CRP ratio (LCR) was calculated as lymphocytes divided by CRP, and the CRP to lymphocyte ratio (CRP/Ly) was computed by CRP divided by lymphocytes. The systemic immune inflammation index (SII) was determined by dividing the product of neutrophils and platelets by lymphocytes. The aggregate index of systemic inflammation (AISI) was calculated as the product of neutrophils, monocytes, and platelets divided by lymphocytes, and the systemic inflammation response index as the product of neutrophils and monocytes divided by lymphocytes.
Statistical analysis
SPSS software (version 27.0, IBM Inc., United States) was utilized for the statistical analysis. Continuous variables were presented as the mean and SD. Categorical variables were reported as frequencies (n) and percentages (%). The Kolmogorov-Smirnov test was conducted to assess the normality of distributions. When deviations from normality were identified, non-parametric methods were employed, including Pearson's χ2 test for categorical variables and the Mann-Whitney U test for continuous variables. An area under the curve (AUC) analysis was performed for variables with statistically significant differences between the observed groups, illustrated using the receiver operating characteristic curve. Additionally, cut-off values were determined, along with their corresponding sensitivity and specificity. Logistic regression analysis was conducted for highly diagnostic-accuracy variables (AUC > 0.7). The level of statistical significance was set at 5% (P ≤ 0.05).
RESULTS
Out of 170 patients, 86 (50.6%) had MACE, while 84 (49.4%) were in the control group. There were no significant differences in age (MACE: 69.5 years, Control: 66 years), weight (MACE: 86.5 kg, Control: 86 kg), height (MACE: 1.71 meters, Control: 1.70 meters), or body mass index (MACE: 28.75, Control: 30.5). However, hypertension was more prevalent in the MACE group (93% vs 82.1%, P = 0.026), and tobacco consumption was higher in the control group (57.1% vs 43%, P = 0.050). Among MACE patients, 40.7% had lethal outcome, while 59.3% had non-lethal events (Table 1).
Table 1 Sociodemographic data, median, median (25th-75th percentiles)/n (%).
Variable
MACE (n = 86)
Control (n = 84)
P value
Age
69.5 (60.0-79.0)
66.0 (60.0-73.0)
0.557
Weight
86.5 (81.0-107.0)
86 (81.0-107.0)
0.287
Height
1.71 (1.64-1.88)
1.70 (1.65-1.84)
0.119
BMI
28.75 (27.2-36.2)
30.5 (27.7-35.8)
0.453
Hypertension
No
6 (7.0)
15 (17.9)
0.026
Yes
80 (93.0)
69 (82.1)
Diabetes mellitus
No
53 (61.6)
46 (54.8)
0.276
Yes
33 (38.4)
38 (45.2)
Hyperlipoproteinemia
No
25 (29.1)
21 (25.0)
0.859
Yes
61 (70.9)
63 (75.0)
Alcohol consumption
No
51 (59.3)
56 (66.7)
0.700
Yes
35 (40.7)
28 (33.3)
Tobacco consumption
No
49 (57.0)
36 (42.9)
0.050
Yes
37 (43.0)
48 (57.1)
MACE
Lethal
35 (40.7)
Non-lethal
51 (59.3)
No differences were observed between the MACE and control groups in leukocytes, erythrocytes, platelets, monocytes, basophils, eosinophils, lymphocytes, or neutrophils at both time points (T1 and T2). However, platelet levels at T1 showed a near difference (P = 0.056), with higher median levels in the MACE group (238.5) compared to the control group (220.0). At T2, CRP levels approached significance (P = 0.051), with higher median levels in the MACE group (30.5) compared to the control group (13.4) (Table 2). Only the MNR at T2 differed significantly between the MACE and control groups (0.111 vs 0.138, P = 0.022). MNR at T2 (Table 3) had poor predictive value for MACE with an AUC of 0.602 (95%CI: 0.516-0.687) (Figure 1A).
Figure 1 Receiver operating curve analysis for hematological-derived ratios with area under curve > 0.7.
A: Monocyte to neutrophil ratio at T2 for major adverse cardiovascular event in non-ST segment elevation myocardial infarction patients; B: Hematological-derived ratios predicting lethal outcomes. CRP/Ly: C-reactive protein-to-lymphocyte ratio; NLPR: Neutrophil-to-lymphocyte and platelet ratio; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio; SII: Systemic immune inflammation index.
Table 2 Primary hematological and inflammatory parameters in studied groups, median (25th-75th percentiles).
Parameter
Time
MACE (n = 86)
Control (n = 84)
P value
Leukocytes
T1
9.9 (7.9-11.9)
9.3 (7.4-11.8)
0.322
T2
9.1 (7.3-11.3)
8.9 (6.7-10.6)
0.264
Erythrocytes
T1
4.5 (4.1-5.0)
4.3 (3.9-4.8)
0.078
T2
4.5 (4.0-4.9)
4.4 (4.0-4.9)
0.581
Platelets
T1
238.5 (187.0-286.0)
220.0 (176.5-253.5)
0.056
T2
240.0 (174.0-283.0)
216.5 (180.0-257.0)
0.287
Monocytes
T1
0.7 (0.5-0.9)
0.7 (0.5-0.9)
0.344
T2
0.7 (0.6-1.0)
0.8 (0.6-0.9)
0.882
Basophils
T1
0.0 (0.0-0.0)
0.0 (0.0-0.1)
0.563
T2
0.0 (0.0-0.0)
0.0 (0.0-0.1)
0.403
Eosinophils
T1
0.0 (0.0-0.1)
0.1 (0.0-0.1)
0.111
T2
0.0 (0.0-0.1)
0.1 (0.0-0.2)
0.321
Lymphocytes
T1
1.6 (1.1-2.1)
1.5 (1.2-2.0)
0.130
T2
1.7 (1.2-2.3)
1.8 (1.2-2.3)
0.090
Neutrophils
T1
7.3 (5.6-9.0)
6.4 (4.7-9.8)
0.611
T2
6.2 (4.9-8.7)
5.8 (4.2-7.5)
0.374
C-reactive protein
T1
7.4 (2.6-30.4)
8.9 (2.2-21.5)
0.215
T2
30.5 (6.3-67.7)
13.4 (5.0-48.5)
0.051
Table 3 Comparative analysis of hematological-derived ratios between major adverse cardiovascular event group and controls, median (25th-75th percentiles).
HDR
Time
MACE
Control
P value
NLR
T1
4.394 (2.974-7.432)
4.179 (2.534-7.715)
0.537
T2
3.804 (2.231-7.092)
3.053 (2.186-4.903)
0.070
dNLR
T1
2.775 (1.803-4.643)
2.258 (1.669-4.204)
0.214
T2
2.486 (1.481-4.377)
1.915 (1.430-3.088)
0.100
NPR
T1
0.031 (0.024-0.041)
0.029 (0.020-0.047)
0.685
T2
0.028 (0.020-0.042)
0.024 (0.018-0.039)
0.103
NLPR
T1
0.020 (0.012-0.032)
0.018 (0.012-0.037)
0.762
T2
0.017 (0.010-0.034)
0.013 (0.009-0.024)
0.086
PLR
T1
152.678 (95.053-238.760)
138.596 (100.865-187.930)
0.597
T2
147.935 (92.642-219.337)
120.218 (93.713-169.146)
0.259
MNR
T1
0.095 (0.060-0.141)
0.119 (0.081-0.145)
0.088
T2
0.111 (0.076-0.158)
0.138 (0.105-0.168)
0.022
MLR
T1
0.432 (0.279-0.639)
0.453 (0.304-0.664)
0.407
T2
0.441 (0.285-0.628)
0.389 (0.308-0.628)
0.692
LMR
T1
2.315 (1.564-3.586)
2.207 (1.507-3.286)
0.407
T2
2.270 (1.593-3.504)
2.572 (1.592-3.243)
0.692
LCR
T1
0.180 (0.041-0.642)
0.180 (0.046-0.800)
0.551
T2
0.103 (0.021-0.356)
0.139 (0.031-0.391)
0.194
CRP/Ly
T1
5.539 (1.418-24.320)
5.347 (1.233-20.531)
0.556
T2
9.664 (2.813-47.006)
7.172 (2.559-32.454)
0.194
SII
T1
1044.079 (588.656-1812.658)
933.499 (553.663-1471.157)
0.355
T2
935.137 (467.116-1778.563)
636.296 (458.472-1214.234)
0.071
AISI
T1
730.143 (392.295-1399.338)
619.153 (367.070-1231.876)
0.663
T2
645.503 (306.489-1525.542)
509.665 (265.857-831.593)
0.121
SIRI
T1
2.795 (1.767-4.904)
2.955 (1.585-5.844)
0.968
T2
2.576 (1.511-6.067)
2.124 (1.359-4.433)
0.144
HDRs showed significant differences between NSTEMI patients with lethal and non-lethal outcomes (Table 4). The NLR was higher in lethal outcomes with medians of 7.432 [interquartile range (IQR): 4.542-12.551] at T1 and 6.934 (IQR: 3.672-12.165) at T2, compared to 3.816 (IQR: 2.423-5.783) and 2.794 (IQR: 2.167-5.580) in non-lethal outcomes (P < 0.001). PLR was also higher in lethal outcomes, with medians of 238 (IQR: 150.420-303.448) at T1 and 195.349 (IQR: 149.359-353.846) at T2, vs 124.887 (IQR: 92.446-191.566) and 122.619 (IQR: 83.529-169.186) in non-lethal outcomes (P = 0.007 and 0.001). Conversely, MNR was higher in non-lethal outcomes, with medians of 0.111 (IQR: 0.072-0.144) at T1 and 0.131 (IQR: 0.099-0.172) at T2, compared to 0.067 (IQR: 0.054-0.107) and 0.074 (IQR: 0.043-0.112) in lethal outcomes (P = 0.028 and < 0.001).
Table 4 Comparative analysis of hematological-derived indices among non-ST segment elevation myocardial infarction patients with major adverse cardiovascular event with lethal and non-lethal outcome, median (25th-75th percentiles).
HDR
Time
Lethal outcome (n = 35)
Non-lethal outcome (n = 51)
P value
NLR
T1
7.432 (4.542-12.551)
3.816 (2.423-5.783)
< 0.001
T2
6.934 (3.672-12.165)
2.794 (2.167-5.580)
< 0.001
dNLR
T1
3.955 (2.721-6.764)
2.618 (1.667-3.675)
0.009
T2
3.142 (2.056-5.686)
2.124 (1.436-3.295)
0.027
NPR
T1
0.032 (0.028-0.045)
0.030 (0.023-0.038)
0.090
T2
0.031 (0.026-0.053)
0.026 (0.018-0.038)
0.047
NLPR
T1
0.029 (0.021-0.043)
0.016 (0.011-0.030)
0.005
T2
0.035 (0.017-0.056)
0.013 (0.009-0.028)
< 0.001
PLR
T1
238.000 (150.420-303.448)
124.887 (92.446-191.566)
0.007
T2
195.349 (149.359-353.846)
122.619 (83.529-169.186)
0.001
MNR
T1
0.067 (0.054-0.107)
0.111 (0.072-0.144)
0.028
T2
0.074 (0.043-0.112)
0.131 (0.099-0.172)
0.000
MLR
T1
0.609 (0.424-0.892)
0.365 (0.272-0.509)
0.008
T2
0.559 (0.428-0.756)
0.417 (0.282-0.553)
0.028
LMR
T1
1.641 (1.121-2.358)
2.742 (1.966-3.681)
0.008
T2
1.788 (1.324-2.337)
2.400 (1.808-3.549)
0.028
LCR
T1
0.047 (0.015-0.163)
0.371 (0.084-0.748)
0.001
T2
0.027 (0.008-0.102)
0.151 (0.027-0.424)
0.002
CRP/Ly
T1
21.145 (6.137-66.303)
2.321 (1.327-10.517)
0.001
T2
37.403 (9.790-121.186)
6.630 (2.361-37.340)
0.002
SII
T1
1812.658 (950.655-3283.542)
919.518 (561.464-1277.483)
0.001
T2
1778.563 (852.908-2800.333)
673.179 (413.184-1362.656)
0.001
AISI
T1
1399.338 (695.922-2265.644)
536.824 (370.566-910.278)
0.003
T2
1353.896 (625.428-1836.498)
473.738 (293.227-1110.313)
0.011
SIRI
T1
4.511 (2.677-9.560)
2.473 (1.565-3.845)
0.003
T2
4.653 (2.639-9.270)
2.244 (1.482-4.164)
0.009
The AUC analysis for predicting death in NSTEMI patients shows that NLR at T2 has the highest diagnostic performance, with an AUC of 0.811 (95%CI: 0.727-0.859), a cut-off > 4.667, sensitivity of 74.0%, and specificity of 76.72% (P < 0.001), marking it as a strong prognostic marker (Table 5). Other significant indices include CRP/Ly, with AUCs of 0.702 at T1 and 0.718 at T2, AISI with AUCs of 0.675 at T1 and 0.690 at T2, and PLR with AUCs of 0.676 at T1 and 0.719 at T2 (Figure 1B).
Table 5 Area under the curve analysis for observed hematological-derived ratios regarding death.
Variable
Time
AUC/ROC analysis
AUC (95%CI)
Cut-off
Se
Sp
P value
AISI
T1
0.675 (0.599-0.745)
> 1113.861
64.0
76.6
0.004
T2
0.690 (0.615-0.759)
> 911.4
68.0
75.9
0.004
CRP/Ly
T1
0.702 (0.448-0.603)
> 4.737
84.0
53.1
< 0.001
T2
0.718 (0.643-0.784)
> 22.3
72.00
70.34
< 0.001
dNLRT
T1
0.681 (0.606-0.751)
> 2.46
84.0
51.0
0.002
T2
0.671 (0.595-0.741)
> 4.81
44.0
89.0
0.007
LCR
T1
0.698 (0.623-0.766)
≤ 0.202
84.00
52.45
< 0.001
T2
0.699 (0.637-0.774)
≤ 0.041
71.00
69.34
< 0.001
LMRT
T1
0.634 (0.557-0.707)
≤ 1.926
64.00
66.90
0.038
T2
0.638 (0.561-0.710)
≤ 1.952
64.00
69.66
0.033
MLR
T1
0.634 (0.557-0.707)
> 0.509
64.00
66.90
0.039
T2
0.637 (0.560-0.710)
> 0.509
64.00
69.66
0.033
MNR
T1
0.673 (0.597-0.743)
≤ 0.08
64.00
71.03
0.004
T2
0.681 (0.649-0.724)
≤ 0.079
60.00
74.28
< 0.001
NLPR
T1
0.664 (0.588-0.735)
> 0.018
80.00
55.17
0.004
T2
0.757 (0.686-0.819)
> 0.021
68.00
70.34
< 0.001
NLR
T1
0.707 (0.632-0.774)
> 4.076
84.00
51.72
< 0.001
T2
0.811 (0.727-0.859)
> 4.667
74.00
76.72
< 0.001
NPR
T1
0.598 (0.520-0.672)
> 0.028
72.00
48.97
0.072
T2
0.657 (0.580-0.728)
> 0.025
76.00
52.41
0.005
PLR
T1
0.676 (0.600-0.745)
> 230.232
52.00
84.14
0.005
T2
0.719 (0.645-0.785)
> 159.74
72.00
72.41
< 0.001
SII
T1
0.706 (0.631-0.773)
> 1745.18
56.00
82.76
< 0.001
T2
0.744 (0.671-0.808)
> 1400.466
64.00
81.38
< 0.001
SIRI
T1
0.661 (0.584-0.731)
> 3.907
68.00
66.90
< 0.001
T2
0.684 (0.608-0.753)
> 4.164
64.00
74.48
0.003
CRP/Ly at T1 (> 4.737) has an OR of 3.690 (95%CI: 1.140-11.942, P = 0.024), demonstrating strong predictive value. NLR at T1 (> 4.076) and T2 (> 4.667) are also significant predictors, with ORs of 1.300 (95%CI: 1.121-1.743, P = 0.009) and 4.915 (95%CI: 1.917-12.602, P = 0.001) respectively, indicating that NLR at T2 is the most powerful predictor of lethal MACE (Table 6).
Table 6 Logistic regression predictive analysis regarding major adverse cardiovascular events-lethal outcome among patients with non-ST segment elevation myocardial infarction.
Variable
OR
95%CI
P value
Lower
Upper
CRP/Ly (T1) > 4.737
3.690
1.140
11.942
0.024
CRP/Ly (T2) > 22.3
2.839
0.835
9.650
0.095
NLPR (T2) > 0.021
2.780
0.751
10.285
0.126
NLR (T1) > 4.076
1.300
1.121
1.743
0.009
NLR (T2) > 4.667
4.915
1.917
12.602
0.001
PLR (T2) > 159.74
3.262
0.958
11.102
0.059
SII (T1) > 1745.18
2.642
0.650
10.743
0.175
SII (T2) > 1400.466
1.352
0.295
6.205
0.698
DISCUSSION
This study aimed to investigate the predictive role of HDR for MACE, particularly lethal outcomes, in patients with NSTEMI. Significant predictors identified in our study included NLR, NLPR, PLR, and CRP/Ly, with key findings showing that NLR at T2 had the highest diagnostic performance (AUC of 0.811), and CRP/Ly at T1 and T2, AISI, and PLR were also notable predictors. Our findings highlight the important role of inflammation in the etiology of NSTEMI and subsequent MACE occurrences.
Atherosclerosis is a chronic condition characterized by plaque formation in the inner lining of the blood vessels. Cholesterol build-up and inflammation are the main underlying causes of cardiovascular disease. Inflammation has long been recognized as a key factor in atherosclerosis and its complications. Researchers have conducted laboratory and animal studies to explore targeting the inflammatory cascade associated with atherosclerosis. Elevated biomarkers can help identify patients at risk for MACE and guide the appropriate treatment options. CRP is the most promising and widely used biomarker, with extensive research data available[20]. Hematologic parameters are also considered prognostic, considering their role in inflammation. In the present study, the primary hematological parameters, including total leucocyte count and all of its subtypes (monocytes, basophils, eosinophils, lymphocytes, and neutrophils), as well as erythrocytes and platelets, showed no significant differences comparing NSTEMI patients with MACE to a control group. On the other hand, our data showcases significant differences in HDRs between NSTEMI patients who had fatal and non-fatal outcomes following a MACE. Elevated levels of NLR, NLPR, PLR, and CRP/Ly in patients who experienced lethal outcomes reflect inflammatory involvement and provide important prognostic information[21].
NLR was identified as the most potent predictor of MACE. There is a significant increase in mortality risk among patients with NSTEMI who have elevated NLR as a marker of a severe inflammatory disease. Similarly, a meta-analysis that included 9406 patients with ACS and an elevated pretreatment NLR value was useful in predicting MACE occurrence[22-24]. In our study, elevated NLPR levels were found to have predictive potential for predicting mortality at T2. As it is a relatively new biomarker, few studies have investigated its potential in cardiovascular disease. One of the studies is that of Fan et al[25] in which it was observed that an elevated NLPR level is associated with a higher risk of MACE. Their study included NSTEMI patients as well as STEMI patients undergoing percutaneous coronary intervention for the first time. It is interesting to note that the same cut-off value ≥ 0.018 was used in their study, although the sensitivity and specificity was slightly lower at T1 and T2 compared to our study.
In our study, higher values of PLR were seen among patients who suffered MACEs, making it another significant predictor. The median PLR in the fatal outcome group at T1 and T2 was notably higher. Interestingly, elevated PLR is associated with increased thrombotic and inflammatory activity, suggesting its significance as a relevant prognostic marker in ACS, according to a comprehensive review and meta-analysis literature search conducted by Pruc et al[14].
It is well known that CRP is an acute-phase reactant produced by the liver that rises in response to inflammation[26]. Elevated CRP levels reflect systemic inflammation and have been associated with adverse outcomes in cardiovascular diseases[27]. To date, there are not enough studies that have investigated the potential of LCR as a new biomarker for the prediction of MACE in NSTEMI patients. A slightly greater interest has been noted in STEMI patients, as shown in the study by Ye et al[17], in which an association with traditional risk factors such as diabetes, hypertension and smoking was observed, which was also found in our study. In their study, LCR showed high sensitivity and specificity as a predictor of long-term MACEs in STEMI patients at admission and 24 hours after percutaneous coronary intervention, which could contribute to improving the quality of life of these patients. In relation to our research, slightly lower sensitivity and specificity in the T2 category has been reported in NSTEMI patients, and more extensive studies are needed to demonstrate the predictive potential of LCR in these patients.
The CRP/Ly ratio combines this marker with the lymphocyte count, offering a more nuanced view of the inflammatory state. In our study, CRP/Ly at T1 and T2 showed significant predictive value. The AUC for CRP/Ly at T2 was 0.718, indicating its predictive efficacy in identifying inflammation and the probability of adverse outcomes[15,16]. These findings are consistent with research by Gupta et al[28] that found a correlation between the extent of inflammation and myocardial damage and CRP levels, which makes CRP/Ly a useful predictive tool in cardiovascular risk stratification[28].
Nevertheless, a study by Stefano et al[29] suggests a differential inflammatory pattern in NSTEMI patients. The absence of significant correlations between inflammatory indexes and myocardial infarction in NSTEMI supports the hypothesis that a different pattern of inflammation occurs in these patients[29]. These observations indicate that AISI, which combines several inflammatory markers, was also a significant predictor. Although specific median values and ranges were not provided in the summary, the significant P-values (P < 0.001) for both T1 and T2 indicate that AISI effectively captures systemic inflammation and is predictive of adverse cardiovascular events[30].
Inflammatory markers are not fully considered by conventional risk evaluation scores, including widely used Thrombolysis in Myocardial Infarction and Global Registry of Acute Coronary Events scores; instead, they mainly rely upon clinical and biochemical factors. These models could become more predictive and provide a more complete assessment of patient risk if they incorporate NLR, PLR, and CRP/Ly[31,32]. Emerging data supports this strategy by indicating that multi-marker tactics integrate many risk markers and provide better prognosis accuracy than single-marker approaches[33].
It is crucial to use more aggressive therapy options and maintain ongoing, close monitoring if a patient has been identified as having a high risk of MACE and a fatal outcome to achieve a more successful clinical outcome[34]. These inflammatory indicators derived from hematological analysis could be useful in detecting high-risk patients suffering from NSTEMI myocardial infarction early. These indicators are easily collected from routine blood tests; they are widely available, affordable, and simple; hence, they are valuable tools for risk stratification, but their importance needs to be considered and addressed[35].
Despite the valuable insights gained from our study, several limitations must be acknowledged. First, the single-center design may limit the generalizability of our findings, as institutional practices and resources could have influenced the results. Additionally, the relatively small sample size underscores the need for future studies to validate our findings in larger, multi-center cohorts. We also did not fully explore the impact of potential confounding factors, such as concomitant infections or inflammatory diseases, which could affect the interpretation of these markers. Further research should investigate the molecular mechanisms linking inflammation and cardiovascular events to enhance our understanding of the pathophysiological pathways involved[36,37]. Moreover, integrating these markers into existing risk models warrants further exploration, particularly regarding their potential influence on clinical decision-making and patient outcomes. Nonetheless, a notable strength of our study is its prospective nature, enabling systematic data collection and detailed analysis.
CONCLUSION
This study highlights the significant prognostic value of HDIs in predicting MACE among NSTEMI patients. In particular, during follow-up, NLR, PLR, and CRP/Ly offer important insights into the inflammatory processes that underlie cardiovascular events. Enhancing risk categorization and improving patient outcomes may be possible by incorporating these markers into current risk models and therapeutic practices. Validating these results and investigating the molecular pathways connecting inflammation to harmful cardiovascular events should be the main goals of future research.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Medical laboratory technology
Country of origin: Bosnia and Herzegovina
Peer-review report’s classification
Scientific Quality: Grade B
Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade B
P-Reviewer: Hussein AM S-Editor: Liu H L-Editor: A P-Editor: Guo X
Gardarsdottir HR, Sigurdsson MI, Andersen K, Gudmundsdottir IJ. Long-term survival of Icelandic women following acute myocardial infarction.Scand Cardiovasc J. 2022;56:114-120.
[PubMed] [DOI][Cited in This Article: ][Reference Citation Analysis (0)]
Sricholwattana S, Chaipromprasit J, Kosum P. Prevalence and characteristics of non-ST-segment elevation in acute myocardial infarction with insignificant coronary artery disease.Eur Heart J. 2022;43.
[PubMed] [DOI][Cited in This Article: ][Reference Citation Analysis (0)]
Khand A, Frost F, Grainger R, Fisher M, Chew P, Mullen L, Patel B, Obeidat M, Albouaini K, Dodd J. Identification of high-risk non-ST elevation myocardial infarction at presentation to emergency department. A prospective observational cohort study in North West England.BMJ Open. 2020;10:e030128.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 3][Cited by in F6Publishing: 3][Article Influence: 0.8][Reference Citation Analysis (0)]
Siasos G, Lazaros G, Oikonomou E, Zografos T, Athanasiou D, Vavuranakis M, Antonopoulos A, Tsigkou V, Stefanadis C, Papavassiliou AG, Tousoulis D. Different Prognostic Significance of Cardiac Troponin at Presentation and Peak Cardiac Troponin in Patients with Non-ST Segment Elevation Myocardial Infarction.Cardiology. 2016;134:384-388.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 3][Cited by in F6Publishing: 3][Article Influence: 0.4][Reference Citation Analysis (0)]
Segalo S, Kiseljakovic E, Papic E, Joguncic A, Pasic A, Sahinagic M, Lepara O, Sporisevic L. The Role of Hemogram-derived Ratios in COVID-19 Severity Stratification in a Primary Healthcare Facility.Acta Inform Med. 2023;31:41-47.
[PubMed] [DOI][Cited in This Article: ][Cited by in F6Publishing: 1][Reference Citation Analysis (0)]
Tudurachi BS, Anghel L, Tudurachi A, Sascău RA, Stătescu C. Assessment of Inflammatory Hematological Ratios (NLR, PLR, MLR, LMR and Monocyte/HDL-Cholesterol Ratio) in Acute Myocardial Infarction and Particularities in Young Patients.Int J Mol Sci. 2023;24.
[PubMed] [DOI][Cited in This Article: ][Cited by in F6Publishing: 37][Reference Citation Analysis (0)]
Pruc M, Peacock FW, Rafique Z, Swieczkowski D, Kurek K, Tomaszewska M, Katipoglu B, Koselak M, Cander B, Szarpak L. The Prognostic Role of Platelet-to-Lymphocyte Ratio in Acute Coronary Syndromes: A Systematic Review and Meta-Analysis.J Clin Med. 2023;12.
[PubMed] [DOI][Cited in This Article: ][Reference Citation Analysis (0)]
Ye J, Xu D, Yuan R, Cao S, Wang Z, Wang Y, Li C, Zong G. Significance of Multiple Lymphocyte-to-C-Reactive Protein Ratios in Predicting Long-Term Major Cardiovascular Adverse Events in Emergency Percutaneous Coronary Intervention Patients with ST-Segment Elevation Myocardial Infarction.J Inflamm Res. 2024;17:3407-3418.
[PubMed] [DOI][Cited in This Article: ][Reference Citation Analysis (0)]
Fan W, Wei C, Liu Y, Sun Q, Tian Y, Wang X, Liu J, Zhang Y, Sun L. The Prognostic Value of Hematologic Inflammatory Markers in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.Clin Appl Thromb Hemost. 2022;28:10760296221146183.
[PubMed] [DOI][Cited in This Article: ][Cited by in F6Publishing: 4][Reference Citation Analysis (0)]
Pojskić L, Hasić S, Tahto E, Arnautović-Torlak V, Pojskić B. Influence of C-reactive protein on the occurrence and assessing of albuminuria severity in diabetics.Med Glas (Zenica). 2018;15:10-15.
[PubMed] [DOI][Cited in This Article: ][Reference Citation Analysis (0)]
Damen SAJ, Cramer GE, Dieker HJ, Gehlmann H, Aengevaeren WRM, Oude Ophuis TJM, Fokkert MJ, Dikkeschei LD, Vroemen WHM, Verheugt FWA, Brouwer MA, Suryapranata H. A multi-site coronary sampling study on CRP in non-STEMI: Novel insights into the inflammatory process in acute coronary syndromes.Atherosclerosis. 2018;278:117-123.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 6][Cited by in F6Publishing: 5][Article Influence: 0.8][Reference Citation Analysis (0)]
Gupta S, Gupta VK, Gupta R, Arora S, Gupta V. Relationship of high-sensitive C-reactive protein with cardiovascular risk factors, clinical presentation and angiographic profile in patients with acute coronary syndrome: an Indian perspective.Indian Heart J. 2013;65:359-365.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 7][Cited by in F6Publishing: 7][Article Influence: 0.6][Reference Citation Analysis (0)]
Di Stefano R, Di Bello V, Barsotti MC, Grigoratos C, Armani C, Dell'Omodarme M, Carpi A, Balbarini A. Inflammatory markers and cardiac function in acute coronary syndrome: difference in ST-segment elevation myocardial infarction (STEMI) and in non-STEMI models.Biomed Pharmacother. 2009;63:773-780.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 42][Cited by in F6Publishing: 53][Article Influence: 3.5][Reference Citation Analysis (0)]
Suner A, Carr BI, Akkiz H, Uskudar O, Kuran S, Tokat Y, Tokmak S, Ballı T, Ulku A, AkCam T, Delik A, Arslan B, Doran F, YalCın K, Ekinci N, Yilmaz S, Ozakyol A, Yücesoy M, BahCeci HI, Polat KY, Şimsek H, Ormeci N, Sonsuz A, Demir M, KılıC M, Uygun A, Demir A, Altıntas E, Karakulah G, Temel T, Bektas A. Inflammatory markers C-reactive protein and PLR in relation to HCC characteristics.J Transl Sci. 2019;5.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 11][Cited by in F6Publishing: 18][Article Influence: 3.0][Reference Citation Analysis (0)]
Sabatine MS, Morrow DA, de Lemos JA, Gibson CM, Murphy SA, Rifai N, McCabe C, Antman EM, Cannon CP, Braunwald E. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide.Circulation. 2002;105:1760-1763.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 514][Cited by in F6Publishing: 540][Article Influence: 24.5][Reference Citation Analysis (0)]
Sweitzer B. Perioperative Evaluation and Optimization of Patients at Risk of Cardiac Complications for Non-Cardiac Surgery.Mo Med. 2016;113:320-324.
[PubMed] [DOI][Cited in This Article: ]
