Baseline Characteristics
The baseline characteristics of the study participants were shown in Table 1. Over a median of 37.1 months (25th–75th percentile 22.5–55.4 months) follow-up period, 395 CVEs occurred (160 died, 78 suffered non-fatal MI, and 157 had strokes). Patients suffered CVEs tended to be older (p<0.001), with higher prevalence of hypertension (p=0.005), DM (p<0.001), and lower BMI (p=0.016). There was no significant difference regarding the baseline lipid profiles (TG, TC, LDL-C, HDL-C, apoA1, apoB, all p>0.05) except Lp(a) levels (p=0.001). Significantly, the concentration of Fib and D-dimer were higher in patients with CVEs (all p<0.05). Meanwhile, the rate of statin usage was lower(p=0.005) at admission while balanced (p>0.05) at discharge in CVEs compared with patients without events. However, The HR of baseline characteristics with future CVEs were presented in Supplementary Table 1.
Table 1 Baseline characteristics of study patients
|
Total
|
Events
|
No events
|
p value
|
|
n=8417
|
n=395
|
n=8022
|
|
Clinical characteristics
|
|
|
|
|
Age, years
|
57.4±10.8
|
62.2±10.2
|
57.2±10.8
|
<0.001
|
Male sex, (%)
|
71.7
|
71.6
|
71.7
|
0.993
|
BMI (kg/m2)
|
25.8±3.2
|
25.5±3.2
|
25.9±3.2
|
0.016
|
Hypertension, (%)
|
62.0
|
68.8
|
61.7
|
0.005
|
Dyslipidemia, (%)
|
74.8
|
72.3
|
74.9
|
0.259
|
Diabetes Mellitus, (%)
|
27.5
|
37.1
|
27.0
|
<0.001
|
Family history of CAD, (%)
|
13.6
|
14.3
|
13.5
|
0.097
|
Current smoker, (%)
|
54.4
|
54.3
|
54.4
|
0.968
|
Laboratory findings
|
|
|
|
|
TC (mmol/L)
|
4.16±1.17
|
4.17±1.26
|
4.15±1.17
|
0.819
|
LDL-C (mmol/L)
|
2.53±1.01
|
2.53±1.11
|
2.53±1.00
|
0.970
|
HDL-C (mmol/L)
|
1.06±0.29
|
1.05±0.29
|
1.06±0.29
|
0.662
|
TG (mmol/L)
|
1.50(1.10-2.10)
|
1.48(1.06-2.10)
|
1.50(1.10-2.10)
|
0.538
|
Lipoprotein(a) (mg/dL)
|
15.18(6.74-36.79)
|
19.24(9.01-45.58)
|
15.00(6.66-36.26)
|
0.001
|
apoA1 (g/L)
|
1.33±0.29
|
1.34±0.30
|
1.33±0.29
|
0.726
|
apoB (g/L)
|
0.92±0.30
|
0.93±0.31
|
0.92±0.30
|
0.609
|
Fibrinogen(g/L)
|
3.24±0.79
|
3.35±0.81
|
3.23±0.78
|
0.003
|
D-dimer (ug/mL)
|
0.42±0.62
|
0.55±0.66
|
0.42±0.62
|
<0.001
|
Medications at admission
|
|
|
|
|
Statins, (%)
|
75.5
|
68.3
|
75.8
|
0.005
|
Aspirin, (%)
|
83.6
|
82.3
|
83.6
|
0.557
|
ACEI, (%)
|
12.5
|
13.3
|
12.5
|
0.682
|
ARB, (%)
|
12.8
|
10.6
|
12.9
|
0.361
|
β-blockers, (%)
|
48.2
|
48.7
|
48.1
|
0.893
|
CCB, (%)
|
19.2
|
15.9
|
19.3
|
0.228
|
Medications at discharge
|
|
|
|
|
Statins, (%)
|
94.0
|
95.5
|
93.9
|
0.313
|
Aspirin, (%)
|
96.2
|
96.9
|
96.2
|
0.638
|
ACEI, (%)
|
22.2
|
26.3
|
22.0
|
0.096
|
ARB, (%)
|
23.0
|
26.3
|
22.9
|
0.175
|
β-blockers, (%)
|
77.9
|
80.6
|
77.8
|
0.278
|
CCB, (%)
|
38.1
|
35.3
|
38.2
|
0.323
|
Data are expressed as mean ± SD or median (25th–75th percentile) unless otherwise indicated. ACEIs, ACE inhibitors; ARBs, angiotensin receptor blockers; CCB, calcium channel blocker.
Association of plasma Lp(a) Levels and CVEs
In the current analysis, the subjects were assigned to 3 groups according to Lp(a) levels (Lp(a)-L:<10mg/dL, Lp(a)-M:10-29.9mg/dL, Lp(a)-H ≥30mg/dL). As shown in Fig. 1, the prevalence of CVEs in the Lp(a)-L, Lp(a)-M, and Lp(a)-H groups was 3.5%, 5.3%, and 5.6%, respectively (p<0.001). Kaplan-Meier analysis (Fig. 2A) showed that Lp(a)-H subjects had the lowest event-free survival rate among the three groups (p=0.001). As presented in Table 2, univariate Cox regression models showed that Lp(a)-M, and Lp(a)-H group had 1.468-fold and 1.580-fold higher risk of CVEs compared with Lp(a)-L group (Lp(a)-M: HR [95% CI] 1.468 [1.142-1.886], p=0.003); Lp(a)-H: HR[95% CI] 1.580[1.227-2.033], p<0.001). Additional adjustment for other variables in the multivariate Cox regression models did not change the significance of the association (Lp(a)-M: HR[95% CI] 1.531 [1.128-2.079], p=0.006); Lp(a)-H: HR[95% CI] 1.786[1.315-2.426], p<0.001; Table 3).
Table 2 Association of fibrinogen and Lp(a) categories with clinical outcomes
Risk Factor
|
Tertile/Range
|
KM rates(%)
|
Hazard Ratio
|
(95% CI)
|
p value
|
Lp(a) categories
|
Total (mg/dL)
|
|
|
|
<0.001
|
|
Lp(a)-L (<10)
|
3.5
|
Reference
|
|
|
Lp(a)-M (10-29.9)
|
5.3
|
1.468
|
1.142-1.886
|
0.003
|
|
Lp(a)-H (≥30)
|
5.6
|
1.580
|
1.227-2.033
|
<0.001
|
Fibrinogen categories
|
Total (g/L)
|
|
|
|
<0.001
|
|
Fib-L(<2.84)
|
4.0
|
Reference
|
|
|
Fib-M(2.85-3.42)
|
4.4
|
1.123
|
0.867-1.455
|
0.380
|
|
Fib-H(≥3.43)
|
6.1
|
1.631
|
1.282-2.074
|
<0.001
|
Combined categories
|
Total
|
|
|
|
<0.001
|
G1(Lp(a)-L+Fib-L)
|
3.3
|
Reference
|
G2(Lp(a)-L+Fib-M)
|
3.5
|
1.091
|
0.697-1.707
|
0.704
|
G3(Lp(a)-L+Fib-H)
|
4.0
|
1.234
|
0.771-1.977
|
0.381
|
G4(Lp(a)-M+Fib-L)
|
4.1
|
1.164
|
0.741-1.828
|
0.509
|
|
G5(Lp(a)-M+Fib-M)
|
4.9
|
1.406
|
0.914-2.162
|
0.121
|
|
G6(Lp(a)-M+Fib-H)
|
7.0
|
2.135
|
1.446-3.152
|
<0.001
|
|
G7(Lp(a)-H+Fib-L)
|
4.8
|
1.348
|
0.849-2.140
|
0.206
|
|
G8(Lp(a)-H+Fib-M)
|
5.4
|
1.578
|
1.026-2.426
|
0.038
|
|
G9(Lp(a)-H+Fib-H)
|
7.2
|
2.215
|
1.506-3.257
|
<0.001
|
Data are expressed as HR (95%CI). L, low; M, medium, H, high.
Table 3 Adjusted association of fibrinogen and Lp(a) categories with clinical outcomes
Risk Factor
|
Tertile/Range
|
KM rates(%)
|
Hazard Ratio
|
(95% CI)
|
p value
|
Lp(a) categories
|
Total
|
|
|
|
0.001
|
|
Lp(a)-L (<10)
|
3.5
|
Reference
|
|
|
Lp(a)-M (10-29.9)
|
5.3
|
1.531
|
1.128-2.079
|
0.006
|
|
Lp(a)-H (≥30)
|
5.6
|
1.786
|
1.315-2.426
|
<0.001
|
Fibrinogen categories
|
Total
|
|
|
|
0.002
|
|
Fib-L(<2.84)
|
4.0
|
Reference
|
|
|
Fib-M(2.85-3.42)
|
4.4
|
1.001
|
0.726-1.379
|
0.996
|
|
Fib-H(≥3.43)
|
6.1
|
1.558
|
1.162-2.089
|
0.003
|
Combined categories
|
Total
|
|
|
|
0.002
|
|
G1(Lp(a)-L+Fib-L)
|
3.3
|
Reference
|
|
|
G2(Lp(a)-L+Fib-M)
|
3.5
|
1.203
|
0.687-2.107
|
0.518
|
|
G3(Lp(a)-L+Fib-H)
|
4.0
|
1.476
|
0.831-2.619
|
0.184
|
|
G4(Lp(a)-M+Fib-L)
|
4.1
|
1.482
|
0.846-2.596
|
0.169
|
|
G5(Lp(a)-M+Fib-M)
|
4.9
|
1.511
|
0.866-2.636
|
0.146
|
|
G6(Lp(a)-M+Fib-H)
|
7.0
|
2.307
|
1.409-3.777
|
0.001
|
|
G7(Lp(a)-H+Fib-L)
|
4.8
|
1.912
|
1.085-3.369
|
0.025
|
|
G8(Lp(a)-H+Fib-M)
|
5.4
|
1.707
|
0.984-2.962
|
0.057
|
|
G9(Lp(a)-H+Fib-H)
|
7.2
|
2.656
|
1.628-4.333
|
<0.001
|
Data are expressed as HR (95%CI). L, low; M, medium, H, high. Covariates used for adjustment are age, sex, BMI, diabetes mellitus, hypertension, dyslipidemia, family history of CAD, active smoking, D-dimer, and statin treatment.
Association of plasma Fib Levels and CVEs
Similarly, patients were divided into 3 groups according to Fib levels (Fib-L:<2.84g/L, Fib-M:2.85-3.42 g/L, Fib-H:≥3.43 g/L). The prevalence of CVEs in the Fib-L, Fib-M, and Fib-H groups was 4.0%, 4.4%, and 6.1%, respectively (p<0.001). The event-free survival rate was lowest in the Fib-H group (p<0.001, Fig. 2B). Compared to Fib-L group, the Fib-H group had 1.631-fold higher risk of CVEs (HR [95% CI] 1.631 [1.282-2.074], p<0.001) even after adjusting for potential confounders (HR [95% CI] 1.558 [1.162-2.089], p=0.003).
Inter-relationship of Lp(a), Fib Levels and CVEs
To evaluate an interaction between plasma Lp(a) and Fib levels on the risk of CVEs, the subjects were assigned to 9 groups according to Lp(a) and Fib levels (G1(Lp(a)-L+Fib-L, G2(Lp(a)-L+Fib-M, G3(Lp(a)-L+Fib-H, G4(Lp(a)-M+Fib-L, G5(Lp(a)-M+Fib-M, G6(Lp(a)-M+Fib-H, G7(Lp(a)-H+Fib-L, G8(Lp(a)-H+Fib-M, G9(Lp(a)-H+Fib-H).
The occurrence of CVEs in the 9 groups was 3.3%, 3.5%, 4.0%, 4.1%, 4.9%, 7.0%, 4.8%, 5.4%, and 7.2%, respectively (p<0.001, Figure 1). Hazard ratios were calculated for each group using the G1 (group 1, Lp(a)-L and Fib-L) as a reference (Table 2). After adjusting for potential confoundings, the 6th group (Lp(a)-M and Fib-H) and 9th group (Lp(a)-H and Fib-H) had 2.307-fold and 2.656-fold higher risk of CVEs (HR [95% CI] 2.307 [1.409-3.777], p=0.001; 2.656 [1.628-4.333], p<0.001, respectively, Table 3).
In the original model, the C-statistic values were 0.633 (95% CI 0.603-0.664) with traditional risk factors, (Table 4). Addition of Lp(a) categories to the original model induced slightly improvement in C-statistic (ΔC-statistic 0.010 [-0.001-0.023], p= 0.088) but did not reach statistical significance. When added Fib categories to the original model did not improve the C-statistic (ΔC-statistic 0.003 [-0.005-0.012], p= 0.443). Nonetheless, the combined Lp(a) and Fib categories resulted in a slightly improvement in C-statistic (ΔC-statistic 0.013 [0.002–0.027], p=0.033).
Table 4 C-statistic of Lp(a) and Fib categories for predicting CVEs
Models
|
C-statistic (95% CI)
|
ΔC-statistic (95% CI)
|
p value
|
Original model
|
0.633(0.603-0.664)
|
-
|
-
|
Original model + Lp(a) categories
|
0.643(0.612-0.674)
|
0.010(-0.001-0.023)
|
0.088
|
Original model + Fib categories
|
0.637(0.606-0.668)
|
0.003(-0.005-0.012)
|
0.443
|
Original model + combined categories
|
0.647(0.616-0.678)
|
0.013(0.002-0.027)
|
0.033
|
Original model included traditional risk factors as age, sex, BMI, diabetes mellitus, hypertension, dyslipidemia, family history of CAD, active smoking