Subject characteristics
A total of 99 subjects and 222 SVGs were included in this study. There were 79 male subjects and 20 female subjects. There were no differences with regards to demographic characteristics or pre-operative risk factors between the patients who had occluded grafts and patents. Intraoperative data, such as ejection fraction, CBP, and cross-clamp time, were also similar (Table 1). Based on aspirin sensitivity, the subjects were then further classified into three different subgroups: resistant (83 conduits), transient (65 conduits), and sensitive (74 conduits).
Table 1
Baseline Characteristic of this study
Variable
|
|
Occluded (n = 47)
|
Patent (n = 175)
|
p
|
Sex
|
|
|
|
|
Male (79 Subjects)
|
|
37 (20.7%)
|
139 (79.3%)
|
0.916
|
Female (20 Subjects)
|
|
10 (21.7%)
|
39 (78.3%)
|
Age (Years)
|
Median
Min-Max
|
56
(50–74)
|
59
(40–74)
|
0.147
|
Risk Factors
|
|
|
|
|
Hypertension
Dyslipidemia
Diabetes Mellitus
Smoking
|
|
39 (83.0%)
39 (83.0%)
29 (61.7%)
31 (66.0%)
|
145 (82.9%)
136 (77.7%)
103 (58.9%)
123 (70.3%)
|
0.984
0.433
0.724
0.568
|
Ejection Fraction (%)
|
Median
Min-Max
|
54
(43–71)
|
52
(40–71)
|
0.111
|
CPB Times (Minutes)
|
Median
Min-Max
|
87 Minutes
(47–114)
|
79 Minutes
(39–118)
|
0.127
|
Cross Clamp Time (Minutes)
|
Median
Min-Max
|
55 Minutes
(31–84)
|
50 Minutes
(29–89)
|
0.128
|
Role of aspirin resistance in early SVG failure
Of the 222 vein conduits, 175 (78.8%) were patent, and 47 (21.2%) were occluded. It was found that 83 conduits were resistant to aspirin while 139 conduits were sensitive to aspirin. In the sensitive group, 65 subjects (46.8%) transformed into a resistant state on the third day after surgery (transient group). In the resistant group, 34.9% of the total graft was occluded, which was higher compared to values in the transient (16.9%) and sensitive (9.5%) groups. Bivariate analysis was performed to assess the relations in each group about the early SVG thrombosis rate. A strong correlation was seen. It was found that the aspirin resistant group had a significantly increased risk of SVG thrombosis post-CABG (RR = 3.69 (1.72–7.93) and p < 0.001). However, transient aspirin resistance also increased the risk of SVG thrombosis post-CABG (RR = 1.79 (0.74–4.34) and p = 0.191), although the result was not statistically significant (Table 2).
Table 2
Vein Graft Patency in Each PFA Subgroup
|
Occluded
(n = 47)
|
Patent
(n = 175)
|
Total
(n = 222)
|
RR
(95% CI)
|
p
|
Resistant
|
29 (34.9%)
|
54 (65.1%)
|
83 (100%)
|
3.69 (1.72–7.93)
|
P < 0.001
|
Transient
|
11 (16.9%)
|
54 (83.1%)
|
65 (100%)
|
1.79 (0.74–4.34)
|
P = 0.191
|
Sensitive
|
7 (9.5%)
|
67 (90.5%)
|
74 (100%)
|
1.00
|
|
PFA = Platelet Function Analyzer |
Role of inflammation factors in early SVG thrombosis
In this study, IL-6, CRP, and leucocyte were evaluated as representative inflammation factors that contribute to early SVG thrombosis formation.
IL-6
The median pre-operative values of IL-6 were insignificantly different in each group (patent or occluded; p = 0.204) and subgroup (Table 3). Post-operatively, the mean values in each group and subgroup also increased insignificantly (p = 0.582) (Table 3).
Table 3 The Influence of Inflammation Factors towards the formation of early
graft failure
Inflammation Factors
|
Occluded
|
Patent
|
P
|
IL-6
|
|
|
|
|
Pre-operative
|
Median
Min–Max
|
4.90
(1.10–13.40)
|
4.77
(1.10–13.40)
|
0.204
|
6 Hrs Post-operative
|
|
107.20
(67.00–292.00)
|
121.00
(59.28–223.00)
|
0.582
|
Delta IL-6
|
|
103.27
(60.90–287.78)
|
114.29
(55.49–216.90)
|
0.350
|
CRP
|
|
|
|
|
Pre-operative
|
|
2.00
(1.00–13.00)
|
2.00
(1.00–18.00)
|
0.483
|
48 Hrs Post-operative
|
|
89.00
(38.00–155.00)
|
87.00
(34.00–31.00)
|
0.267
|
Delta CRP
|
|
87.00
(32.00–154.00)
|
80.00
(31.00–229.00)
|
0.252
|
Leukocyte
|
|
|
|
|
Pre-operative
|
|
7540
(5940–10430)
|
6990
(4120–14320)
|
0.272
|
48 Hrs Post-operative
|
|
18.600
(13.790–26.100)
|
18.780
(13.420–29.000)
|
0.547
|
Delta Leucocyte
|
|
1.0530,00
(6690–18.770)
|
12.280
(6690–16.750)
|
0.277
|
IL-6 = Interleukin 6; CRP = C-Reactive Protein |
CRP
In the pre-operative analysis, the median CRP values were insignificant (p = 0.483) in each group (Table 3). However, these median values also increased insignificantly in each group and subgroup. These results were further analyzed by plotting a receiver operating characteristics 6t (ROC) curve. The graph analysis showed that the validity of the analysis was 55.3% (45.1–65.5%; p = 0.267), and the cross-section coordinate was 101.5, with 48.9% sensitivity and 80% specificity. The analysis showed that a CRP value of more than 101.5 plays a significant role (p = 0.004) in the formation of early SVG thrombosis, with a relative risk of 2.11 (Table 4).
Table 4
Postoperative CRP analysis based on ROC Cut off towards vein graft patency
CRP Cut-Off
|
Total Graft
|
p
|
RR (95% CI)
|
Occluded
|
Patent
|
> 101.5
|
19
35.2%
|
35
64.8%
|
0.004
|
2.11 (1.29–3.46)
|
≤ 101.5
|
28
16.7%
|
140
83.3%
|
|
|
CRP = C-Reactive Protein |
Table 5
Pre and Post operative IL-6 value in each PFA subgroups
|
|
Transient
|
Sensitive
|
p
|
Pre-Operative IL-6
|
Median
Min-Max
|
4,50
(1,10 − 7,89)
|
5,50
(2,00–12,50)
|
0,242
|
Post-Operative IL-6
|
Median
Min-Max
|
166,70
(88,00-223,00)
|
102,95
59,28–200,00
|
< 0,001
|
IL-6 = Interleukin 6; PFA = Platelet Function Analyzer |
Leucocytes
The median pre-operative and post-operative leucocyte values were insignificantly different (p = 0.227 vs. p = 0.547) in each group (Table 3), although there was an increase in postoperative values. The highest increase was achieved 48 hours post-CABG.
Role of IL-6 in the transformation of aspirin sensitivity from sensitive to transient
Of the 222 vein conduits, 139 were categorized as aspirin-sensitive before the subject underwent CABG. However, 65 of these subjects transformed into a resistant state three days after the surgery, which was later called a transient group.
Table 5
Pre and Post operative IL-6 value in each PFA subgroups
|
|
Transient
|
Sensitive
|
p
|
Pre-Operative IL-6
|
Median
Min-Max
|
4,50
(1,10 − 7,89)
|
5,50
(2,00–12,50)
|
0,242
|
Post-Operative IL-6
|
Median
Min-Max
|
166,70
(88,00-223,00)
|
102,95
59,28–200,00
|
< 0,001
|
IL-6 = Interleukin 6; PFA = Platelet Function Analyzer |
Table 6
Prevalence of post-operative IL-6 value in transient aspirin subgroup towards the occurrence of early graft failure in comparison with sensitive subgroup
IL-6 in Transient and Sensitive subgroup
|
Occluded
|
Patent
|
p
|
RR (95% CI)
|
IL-6 > 122,5
|
|
|
|
|
Transient
|
9 (17.3%)
|
43 (82.7%)
|
0.029
|
8.6 (1.28–141.86)
|
Sensitive
|
0 (0.0%)
|
23 (100.0%)
|
|
|
IL-6 ≤ 122,5
|
|
|
|
|
Transient
|
2 (15.4%)
|
11 (84.6%)
|
0.589
|
1.12 (0.26–4.77)
|
Sensitive
|
7 (13.7%)
|
44 (86.3%)
|
|
|
IL-6 = Interleukin 6 |
As stated in the previous analysis, the pre-operative IL-6 values did not differ between the sensitive and transient subgroups (p = 0.242). However, a contrasting result was found postoperatively, with values of 102.95 (59.29–200.00) in the sensitive group and 166.70 (88.00–223.00; p < 0.001) in the transient group (Table 5). These median values in the sensitive and transient subgroups were significantly different. They were then plotted to the ROC curve to calculate the area under the curve (AUC) as the basis of a prognostic model. The result was an AUC of 75.3% (68.3%–82.1%; p < 0.001), with 80% sensitivity and 70.7% specificity.
A cut-off point of 122.5 was used to divide the IL-6 group into two new subgroups: IL-6 > 122.5 and IL-6 ≤ 122.5 (p = 0.210). According to the previous separated analysis, both IL-6 values >122.5 and ≤ 122.5 were not related to the occurrence of early vein graft occlusions. Furthermore, the transient subgroup alone was also not related to the occurrence of early graft patency (p = 0.191). However, this study sought to analyze both variables, and it was found that SVG occlusion was more prevalent in subjects in the transient group where IL-6 > 122.5 (RR = 8.6, p = 0.029) than in the group where IL-6 ≤ 122.5 (RR = 1.12; p = 0.589) when each was compared to the sensitive group with the same IL-6 values (Table 6).
Role of mechanical factors in the formation of early vein graft occlusion
The lower intra-operative blood flow group had a greater prevalence of early graft occlusion than those with the higher flow. However, the differences did not reach statistical significance (24.4% vs. 17.5%; p = 0.210). The pulsatility index and native vessel diameter also failed to discriminate between the occluded and patent grafts (pulsatility index < 3 with 18.2% occlusion vs. PI 3–5 with 25.9%, p = 0.176; diameter 1–1.5mm with 20.5% vs. D >1.5mm with 21.6%, p = 0.846) (Table 7).
Table 7
Role of Mechanical Factors in the formation of early vein graft occlusion
Mechanical Factors
|
Occluded
|
Patent
|
p
|
RR (95% CI)
|
Native Vessel Diameter (mm)
|
|
|
|
|
1.00–1.50
|
17 (20.5%)
|
66 (79.5%)
|
0.846
|
0.95 (0.56–1.61)
|
> 1.50
|
30 (21.6%)
|
109 78.4%)
|
|
|
Mean Graft Flow (MGF) (mL/Sec)
|
|
|
|
|
10–30
|
29 (24.4%)
|
90 (75.6%)
|
0.210
|
1.39 (0.82–2.36)
|
> 30
|
18 (17.5%)
|
85 (82.5%)
|
|
|
Pulsatility Index (PI)
|
|
|
|
|
3–5
|
22 (25.9%)
|
63 (74.1%)
|
0.176
|
1.42 (0.86–2.35)
|
< 3
|
25 (18.2%)
|
112 (81.8%)
|
|
|
PI = Pulsatility Index; MGF = Mean Graft Flow |
Multivariate analysis
Cox regression was used in performing the multivariate statistical analysis, following the backward stepwise method. There were 10 included variables with p ≤ 0.25, which were suspected of contributing to the occurrence of early vein graft occlusion.
Based on the Wald test results, when the p-value of a variable was > 0.10, the variable had to be eliminated in the next step. However, if the p-value were < 0.10, the corresponding variable would be included in the next step.
As a result, there were two critical variables: PFA category resistant, with p<0.001, and PFA category transient, with p = 0.191, regarding the occurrence of early vein graft failure six weeks after CABG. In this study, the formula used to calculate the probability of early vein graft occlusion six weeks after CABG was as follows:
y = -2.259 + 1.637 × PFA Category Resistant + 0.668 × PFA Category Transient
The probabilities of early vein graft occlusion six weeks after CABG were 34.9% in the resistant group, 16.9% in the transient group, and 9.5% in the sensitive group. The relative risk of the occurrence of early vein graft thrombosis was calculated by comparing the probabilities of the resistant and sensitive groups, and the result was 3.69 times more likely to develop early graft failure.