Hemogram-derived ratios as prognostic markers for major adverse cardiovascular events in patients with non-ST-segment elevation myocardial infarction

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.

Key Words: Hemogram-derived ratios; Prognostic markers; Neutrophil-to-lymphocyte ratio; Myocardial infarction

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.

INTRODUCTION

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 (25^th-75^th 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)

BMI: Body mass index; MACE: Major adverse cardiovascular event.

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 (25^th-75^th 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

MACE: Major adverse cardiovascular event.

Table 3 Comparative analysis of hematological-derived ratios between major adverse cardiovascular event group and controls, median (25^th-75^th 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

HDR: Hematological-derived ratios; NLR: Neutrophil-to-lymphocyte ratio; dNLR: Derived neutrophil-to-lymphocyte ratio; NPR: Neutrophil-to-platelet ratio; NLPR: Neutrophil-to-lymphocyte and platelet ratio; PLR: Platelet-to-lymphocyte ratio; MNR: Monocyte to neutrophil ratio; MLR: Monocyte/lymphocyte ratio; LMR: Lymphocyte-to-monocyte ratio; LCR: Lymphocyte to C-reactive protein ratio; CRP/Ly: C-reactive protein-to-lymphocyte ratio; SII: Systemic immune inflammation index; AISI: Aggregate index of systemic inflammation; SIRI: Systemic inflammation response index; T1: Analysis at admission; T2: Analysis after 24 hours.

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 (25^th-75^th 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

HDR: Hematological-derived ratios; NLR: Neutrophil-to-lymphocyte ratio; dNLR: Derived neutrophil-to-lymphocyte ratio; NPR: Neutrophil-to-platelet ratio; NLPR: Neutrophil to lymphocyte and platelet ratio; PLR: Platelet-to-lymphocyte ratio; MNR: Monocyte to neutrophil ratio; MLR: Monocyte/lymphocyte ratio; LMR: Lymphocyte-to-monocyte ratio; LCR: Lymphocyte to C-reactive protein ratio; CRP/Ly: C-reactive protein-to-lymphocyte ratio; SII: Systemic immune inflammation index; AISI: Aggregate index of systemic inflammation; SIRI: Systemic inflammation response index; T1: Analysis at admission; T2: Analysis after 24 hours.

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

HDR: Hematological-derived ratios; NLR: Neutrophil-to-lymphocyte ratio; dNLR: Derived neutrophil-to-lymphocyte ratio; NPR: Neutrophil-to-platelet ratio; NLPR: neutrophil to lymphocyte and platelet ratio; PLR: Platelet-to-lymphocyte ratio; MNR: Monocyte to neutrophil ratio; MLR: Monocyte/lymphocyte ratio; LMR: Lymphocyte-to-monocyte ratio; LCR: Lymphocyte to C-reactive protein ratio; CRP/Ly: C-reactive protein-to-lymphocyte ratio; SII: Systemic immune inflammation index; AISI: Aggregate index of systemic inflammation; SIRI: Systemic inflammation response index; T1: Analysis at admission; T2: Analysis after 24 hours; AUC: Area under the curve; ROC: Receiver operating characteristic.

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

NLR: Neutrophil-to-lymphocyte ratio; NLPR: Neutrophil-to-lymphocyte and platelet ratio; PLR: Platelet-to-lymphocyte ratio; CRP/Ly: C-reactive protein-to-lymphocyte ratio; SII: Systemic immune inflammation index; T1: Analysis at admission; T2: Analysis after 24 hours; OR: Odds ratio.

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.