A Novel Biomarker Scoring System Alone or in Combination with the GRACE Score for the Prognostic Assessment in Non-ST-Elevation Myocardial Infarction

Figures & data

Table 1 Baseline Characteristics and Biomarkers of NSTEMI Patients

Characteristics	All Cohort (n=6076)	Primary Endpoints at 24 Months		P value	Mean/Median Difference 95% CI	OR (95% CI)
		No Event (n=5210)	Event (n=866)
Age, years	66 [59–73]	65 [59–72]	68 [60–76]	<0.001	((-3)–(-1))
Male	4439 (73.1)	3773 (72.4)	666 (76.9)	0.006		0.788 (0.666–0.934)
BMI, kg/m^2	24.72±3.58	24.72±3.58	24.66±3.55	0.460	((-0.20)–0.32)
Smoker	2644 (43.5)	2294 (44.0)	350 (40.4)	0.047		1.160 (1.002–1.343)
Hypertension	3004 (49.4)	2531 (48.6)	473 (54.6)	0.001		0.785 (0.679–0.907)
Systolic blood pressure, mmHg	139.38±14.71	139.73±14.43	137.26±16.11	<0.001	(1.32–3.61)
Diabetes mellitus	1570 (25.8)	1305 (25.0)	265 (30.6)	0.001		0.758 (0.647–0.887)
Family history of coronary artery disease	84 (1.4)	74 (1.4)	10 (1.2)	0.535		1.233 (0.635–2.397)
Killip Class
I	5366 (89.1)	4667 (89.6)	749 (86.5)	0.007		1.343 (1.084–1.663)
II	490 (8.1)	411 (7.9)	79 (9.1)	0.217		0.853 (0.663–1.098)
III or IV	170 (2.8)	132 (2.5)	38 (4.4)	0.002		0.566 (0.392–0.819)
No. of narrowed coronary arteries
1	3274 (53.9)	2845 (54.6)	429 (49.5)	0.006		1.225 (1.061–1.415)
2	1874 (30.8)	1604 (30.8)	270 (31.2)	0.818		0.982 (0.841–1.147)
3	928 (15.3)	761 (14.6)	167 (19.3)	<0.001		0.716 (0.595–0.862)
LEVF, %	52.10±10.97	52.87±10.81	50.03±11.07	0.015	(1.10–4.28)
Prior myocardial infarction	494 (8.1)	406 (7.8)	88 (10.2)	0.018		0.747 (0.586–0.952)
Previous PCI	872 (14.4)	740 (14.2)	132 (15.2)	0.419		0.921 (0.753–1.125)
Previous CABG	447 (7.4)	369 (0.7)	78 (0.9)	<0.001		0.770 (0.596–0.994)
Baseline medications
DAPT	6003 (98.8)	5153 (98.9)	850 (98.2)	0.059		1.289 (0.748–2.222)
β-blockers	4346 (71.5)	3756 (72.1)	590 (68.1)	0.017		1.208 (1.035–1.411)
ACEI or ARBs	3948 (65.1)	3392 (65.1)	556 (64.2)	0.606		1.040 (0.895–1.209)
Statins	5896 (97.0)	5059 (97.1)	837 (96.7)	0.469		1.161 (0.775–1.739)
GRACE scores	126 [111.25–144]	124 [109–142]	139 [120–158]	<0.001	((-16)–(-12))
TIMI scores	2.80±1.14	2.81±1.15	3.17±1.19	<0.001	((-0.44)–(-0.27))
cTnT >10 ng/mL	99 (1.6)	71 (1.4)	28 (3.2)	<0.001		0.413 (0.265–0.644)
cTnT within the limit of detection, ng/mL	1.98±1.96	1.98±1.96	1.95±1.97	0.672	((-0.11)–0.17)
WBC, ×10^9/L	6.75 [5.49–8.41]	6.65 [5.46–8.22]	7.47 [5.80–9.54]	<0.001	((-0.88)–(-0.53))
PLT, ×10^9/L	200 [165–238]	199.00 [164.00–237.00]	203.50 [166.75–244.00]	0.047	((-8.00)–0)
Hb (male), g/L	136.85±16.90	136.95±16.75	135.88±17.69	0.074	((-0.67)–3.45)
Hb (female), g/L	122.14±14.10	122.40±13.83	120.23±15.77	0.065	((-1.19)–4.25)
APTT, s	27.65±3.83	27.59±3.89	27.98±3.44	0.006	((-0.66)–(-0.11))
PT, s	11.30 [10.80–11.90]	11.30 [10.80–11.80]	11.45 [10.90–12.10]	<0.001	((-0.30)–(-0.10))
TT, s	17.44±2.65	17.48±2.82	17.25±1.23	0.020	(0.04–0.42)
INR	1.03±0.17	1.02±0.17	1.05±0.16	<0.001	((-0.04)–(-0.01))
FIB, mg/dL	292.40 [248–355]	286.40 [244.70–346.10]	333.05 [277.88–413.40]	<0.001	((-51.60)–(-39.10))
D-D, mg/L	0.27 [0.19–0.52]	0.26 [0.19–0.49]	0.34 [0.19–0.75]	<0.001	((-0.60)–(-0.30))
CK, U/L	93 [65–163]	90.00 [64.00–145.00]	148.50 [76.00–426.75]	<0.001	((-49.00)–(-33.00))
CK-MB, U/L	16 [12.25–23]	15.00 [12.00–21.00]	23 [15.00–53.00]	<0.001	((-8.00)–(-6.00))
NT-proBNP, pg/mL	192 [71.43–658.15]	166.05 [65.68–541.18]	545.00 [151.40–2077.25]	<0.001	((-293.40)–(-193.90))
hsCRP, mg/L	1.90 [0.69–7.36]	1.69 [0.65–6.19]	4.80 [1.38–19.27]	<0.001	((-2.28)–(-1.48))
HbA1c, %	6.00 [5.60–6.90]	6.00 [5.60–6.90]	6.10 [5.70–7.10]	0.006	((-0.20)–0)
UA, μmol/L	340.90 [280–406]	338.00 [279.00–402.00]	357.00 [284.78–437.00]	<0.001	((-25.00)–(-10.50))
eGFR, mL/min^−1·1.73 m^2	83.14 [67.31–93.30]	83.88 [68.52–93.53]	78.69 [60.25–92.06]	<0.001	(2.94–5.82)
sCr, μmol/L	79 [67.23–94]	79.00 [67.00–93.00]	84.00 [70.00–102.00]	<0.001	((-7.00)–(-3.90))
ALB, g/L	41.14±4.36	41.32±4.29	40.02±4.61	<0.001	(0.99–1.62)
TC, mmol/L	3.86±1.11	3.83±1.10	3.98±1.13	<0.001	((-0.23)–(-0.07))
HDL-C, mmol/L	1.08±0.31	1.09±0.31	1.05±0.30	<0.001	(0.03–0.07)
LDL-C, mmol/L	2.19 [1.66–2.94]	2.16 [1.64–2.88]	2.44 [1.74–3.19]	<0.001	((-0.27)–(-0.13))

Notes: Variables are expressed as number (percentage), mean ± standard deviation or median [inter-quartile range]. For continuous data, the 95% confidence intervals (CI) of mean or median difference were assessed by Student t-test or the Hodges–Lehmann estimate based on Mann–Whitney U-test. For qualitative data, the odds ratios with 95% CI were reported.

Abbreviations: LEVF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft surgery; DAPT, dual antiplatelet therapy; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; cTnT, cardiac troponin T; WBC, white blood cell count; PLT, platelet count; Hb, hemoglobin; APTT, activated partial thromboplastin time; PT, prothrombin time; TT, thrombin time; INR, international normalized ratio; FIB, fibrinogen; D-D, D-dimer; CK, creatine kinase; NT-proBNP, N-terminal pro-B-type natriuretic peptide; hsCRP, high-sensitivity C-reactive protein; HbA1c, hemoglobin A1c; UA, uric acid; eGFR, estimated glomerular filtration rate; sCr, serum creatinine; ALB, albumin; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

Table 2 Cox Proportional Hazard Regression Analyses for the Composite Point of All-Cause Death and Non-Fatal MACEs at 2 Years

Variables	Univariate Analysis		Multivariate Analysis
	HR (95% CI)	P value	HR (95% CI)	P value
WBC	1.035 (1.027–1.043)	<0.001
PLT	1.001 (1.000–1.002)	0.040
APTT	1.019 (1.006–1.032)	0.005
PT	1.147 (1.100–1.196)	<0.001
TT	0.868 (0.816–0.924)	<0.001
INR	1.810 (1.361–2.406)	<0.001
FIB	1.004 (1.003–1.004)	<0.001	1.003 (1.002–1.004)	<0.001
D-D	1.091 (1.056–1.128)	<0.001
CK	1.000 (1.000–1.001)	<0.001	1.000 (1.000–1.000)	<0.001
CK-MB	1.003 (1.003–1.004)	<0.001	1.003 (1.002–1.004)	<0.001
NT-proBNP	1.000 (1.000–1.000)	<0.001	1.000 (1.000–1.000)	<0.001
hsCRP	1.006 (1.005–1.007)	<0.001
HbA1c	1.073 (1.024–1.125)	0.003
UA	1.002 (1.001–1.002)	<0.001	1.001 (1.000–1.002)	0.004
eGFR	0.989 (0.986–0.992)	<0.001
ALB	0.941 (0.928–0.955)	<0.001
TC	1.112 (1.052–1.175)	<0.001
LDL-C	1.208 (1.135–1.287)	<0.001	1.155 (1.077–1.239)	<0.001
HDL-C	0.581 (0.461–0.733)	<0.001	0.599 (0.467–0.769)	<0.001

Notes: The HR and 95% CI were calculated using univariate Cox regression, and variables with statistical significance of P<0.05 were entered into backward stepwise Cox proportional hazard regression model with adjustment for GRACE scores and cTnT. Results in multivariate regression showed the final model after backward elimination process.

Abbreviations: MACE, major adverse cardiac events; HR, hazard ratio; CI, confidence interval; WBC, white blood cell count; PLT, platelet count; Hb, hemoglobin; APTT, activated partial thromboplastin time; PT, prothrombin time; TT, thrombin time; INR, international normalized ratio; FIB, fibrinogen; D-D, D-dimer; CK, creatine kinase; NT-proBNP, N-terminal pro-B-type natriuretic peptide; hsCRP, high-sensitivity C-reactive protein; HbA1c, hemoglobin A1c; UA, uric acid; eGFR, estimated glomerular filtration rate; ALB, albumin; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

Table 3 Final Biomarker Risk Score

Variable	Points
FIB, mg/dL
≤274.0	0
274.1–313.4	+1
≥313.5	+2
CK, U/L
≤202	0
≥203	+1
CK-MB, U/L
≤18	0
19–27	+2
≥28	+3
NT-proBNP, pg/mL
≤934.7	0
≥934.8	+2
UA, μmol/L
≤423	0
≥424	+1
LDL-C, mmol/L
≤3.14	0
≥3.15	+1
HDL-C, mmol/L
≤0.82	+2
0.83–0.96	+1
≥0.97	0
Score range	0–12

Abbreviations: FIB, fibrinogen; CK, creatine kinase; NT-proBNP, N-terminal pro-B-type natriuretic peptide; UA, uric acid; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.

Figure 1 (A) Distribution of biomarker scores; (B) Distribution of GRACE scores; (C) Annual event rate of biomarker scores; (D) Annual event rate of GRACE scores.

Abbreviation: MACE, non-fatal major adverse cardiac events.

Table 4 Prognostic Discrimination

Death at 2 Years	C-Statistic (95% CI)	Categorical NRI (95% CI)^a	Continuous NRI (95% CI)	IDI
GRACE score^b	0.714 (0.671–0.756)**	Reference	Reference	Reference
+FIB	0.776 (0.741–0.811)**	0.125 (−0.031–0.261)	0.082 (0.011–0.189)*	0.015 (0.006–0.023)**
+CK	0.739 (0.700–0.778)**	0.061 (0.030–0.089)*	0.071 (−0.043–0.192)	0.009 (0.002–0.015)**
+CK-MB	0.793 (0.759–0.827)**	0.136 (0.095–0.202)**	0.152 (0.060–0.267)**	0.019 (0.010–0.027)**
+NT-proBNP	0.802 (0.767–0.837)**	0.209 (0.088–0.344)**	0.248 (0.153–0.387)**	0.025 (0.009–0.040)**
+UA	0.735 (0.694–0.776)*	0.002 (−0.096–0.109)	0.069 (0.001–0.117)*	0.005 (−0.011–0.021)
+LDL-C	0.736 (0.694–0.777)*	0.047 (−0.056–0.114)	0.058 (0.007–0.122)*	0.003 (−0.001–0.007)
+HDL-C	0.723 (0.680–0.765)*	0.034 (−0.071–0.116)	0.065 (0.024–0.118)*	0.004 (−0.009–0.015)
Biomarker score^c	0.836 (0.801–0.871)**	0.465 (0.263–0.758)**	0.363 (0.227–0.453)**	0.058 (0.049–0.066)**
GRACE with biomarker score^d	0.851 (0.820–0.882)**	0.552 (0.281–0.761)**	0.416 (0.309–0.531)**	0.064 (0.051–0.075)**
MACE at 2 years
GRACE score^b	0.623 (0.600–0.646)	Reference	Reference	Reference
+FIB	0.660 (0.639–0.681)**	0.089 (0.037–0.159)*	0.040 (−0.001–0.102)	0.010 (0.004–0.015)*
+CK	0.680 (0.658–0.702)**	0.156 (0.092–0.249)**	0.105 (0.055–0.163)**	0.018 (0.012–0.024)**
+CK-MB	0.689 (0.668–0.710)**	0.199 (0.122–0.273)**	0.183 (0.121–0.237)**	0.021 (0.013–0.028)**
+NT-proBNP	0.663 (0.641–0.685)**	0.114 (0.039–0.187)*	0.135 (0.078–0.183)**	0.017 (0.002–0.031)*
+UA	0.637 (0.614–0.659)*	0.031 ((-0.016)–0.080)	0.053 (0.016–0.078)*	0.004 ((-0.002)–0.009)
+LDL-C	0.631 (0.608–0.654)*	0.041 (0.005–0.075)*	0.037 (0.017–0.063)**	0.002 ((-0.002)–0.005)
+HDL-C	0.643 (0.621–0.665)**	0.045 (0.016–0.076)*	0.032 (0.009–0.060)*	0.007 (0.002–0.015)*
Biomarker score	0.697 (0.674–0.719)**	0.228 (0.155–0.376)**	0.246 (0.183–0.321)**	0.036 (0.027–0.042)**
GRACE with biomarker score	0.721 (0.702–0.741)**	0.285 (0.215–0.390)**	0.278 (0.174–0.373)**	0.049 (0.041–0.056)**

Notes: ^aThe categorical NRI for all-cause death and non-fatal MACEs was evaluated at a range of thresholds from 0.02 to 0.08 and 0.10 to 0.20, respectively. ^bThe score for each biomarker was assessed individually on top of the GRACE score. ^cCompared with GRACE scores alone. ^dThe combination of GRACE and biomarker scores compared with GRACE scores alone. *P<0.05; **P<0.001.

Abbreviations: NRI, net reclassification improvement; IDI, integrated discrimination improvement; FIB, fibrinogen; CK, creatine kinase; NT-proBNP, N-terminal pro-B-type natriuretic peptide; UA, uric acid; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.