3.1. Baseline Characteristics
The follow-up of 1,943 patients was completed. Among them, 1,161 cases (59.75%) were with hypertension, 634 cases (32.63%) were with diabetes, 319 cases (16.42%) were with hyperlipidemia, 635 cases (32.68%) were with a smoking history, 363 cases (18.68%) were with a drinking history, and 1,858 cases (95.63%) were regular medication users. There was no statistically significant difference between the baseline characteristics of normal metabolism, intermediate metabolism, and poor metabolism groups, respectively (Table 2). There was also no statistically significant difference, between the baseline characteristics of the abnormal metabolism adopted group and the abnormal metabolism unadopted group (Table 3).
Table 2 The Baseline Characteristics of Metabolic Group
Item/Group
|
Normal metabolic
|
Intermediate metabolic
|
Poor metabolic
|
p-value
|
Age
|
63.39±10.83
|
63.63 ± 10.57
|
63.12 ± 10.87
|
0.060
|
BMI
|
24.18±5.65
|
24.13 ± 6.57
|
24.26 ± 7.38
|
0.848
|
Biochemical indicators
|
PLT (×10^9/L)
|
226.29±59.20
|
225.68 ± 59.58
|
226.53 ± 60.29
|
0.322
|
ALT (U/L)
|
28.97±24.42
|
28.67 ± 22.93
|
29.15 ± 22.98
|
0.868
|
AST (U/L)
|
34.02±36.63
|
33.48 ± 34.04
|
33.54 ± 34.05
|
0.081
|
BUN
|
6.51±5.30
|
6.58 ± 5.81
|
6.43 ± 6.25
|
0.733
|
CREA
|
93.78±54.99
|
94.29 ± 55.60
|
94.94 ± 60.70
|
0.343
|
Interventional situation
|
Average number of implanted stents
|
2.07±1.62
|
2.02 ± 1.55
|
2.03 ± 1.58
|
0.400
|
Gender (Male n (%) )
|
575 (78.12)
|
741 (79.33)
|
210 (76.92)
|
0.654
|
Gender (Female n (%) )
|
161 (21.88)
|
193 (20.67)
|
63 (23.08)
|
Previous history
|
Hypertension n (%)
|
440 (59.78)
|
554 (59.31)
|
167 (61.17)
|
0.859
|
Diabetes n (%)
|
244 (33.15)
|
304 (32.55)
|
86 (31.54)
|
0.882
|
Hyperlipidemia n (%)
|
129 (17.53)
|
146 (15.63)
|
44 (16.12)
|
0.577
|
Smoking history n (%)
|
246 (33.42)
|
297 (31.80)
|
92 (33.70)
|
0.725
|
Drinking history n (%)
|
126 (17.12)
|
184 (19.70)
|
53 (19.41)
|
0.384
|
Medication compliance:
|
|
|
|
|
Regular medication n (%)
|
703 (95.52)
|
892 (95.50)
|
263 (96.34)
|
0.825
|
Table 3 The Baseline Characteristics of the Abnormal Metabolic Groups
Item/
group
|
Adopted
|
Unadopted
|
p-value
|
Intermediate Metabolica (n=196)
|
Poor Metabolicb (n=31)
|
Intermediate Metabolicc (n=738)
|
Poor Metabolicd
(n=242)
|
Age
|
62.97±11.05
|
63.80±10.49
|
63.80±10.44
|
63.03±10.92
|
0.348
|
BMI
|
23.89±4.80
|
23.96±5.22
|
24.20±6.96
|
24.30±7.61
|
0.239
|
Biochemical indicators
|
|
PLT
(×10^9/L)
|
225.32±57.44
|
226.44±57.48
|
225.78±60.13
|
226.54±60.63
|
0.291
|
ALT (U/L)
|
28.80±26.19
|
29.58±27.46
|
28.64±21.99
|
29.10±22.36
|
0.216
|
AST (U/L)
|
33.99±38.77
|
34.20±40.43
|
33.34±32.68
|
33.45±33.17
|
0.751
|
BUN
|
6.65±4.34
|
6.47±4.34
|
6.56±6.14
|
6.43±6.45
|
0.178
|
CREA
|
94.97±56.48
|
96.09±63.46
|
94.11±55.36
|
94.79±60.35
|
0.089
|
Interventional situation
|
|
|
Average number of implanted stents
|
1.99±1.54
|
1.99±1.58
|
2.03±1.55
|
2.03±1.58
|
0.693
|
|
|
|
|
|
p-value (a+c/
b+d)
|
p-value (a+b/
c+d)
|
Gender (Male n (%) )
|
155 (79.08)
|
23 (74.91)
|
586 (79.40)
|
187 (77.27)
|
0.391
|
0.878
|
Gender (Female n (%) )
|
41 (20.92)
|
8 (25.81)
|
152 (20.60)
|
55 (22.73)
|
Previous history
|
|
|
Hypertension n (%)
|
117 (59.69)
|
20 (64.52)
|
437 (59.21)
|
147 (60.74)
|
0.582
|
0.975
|
Diabetes n (%)
|
64 (32.65)
|
10 (32.26)
|
240 (32.52)
|
76 (31.40)
|
0.745
|
0.999
|
Hyperlipidemia n (%)
|
29 (14.80)
|
5 (16.13)
|
117 (15.85)
|
39 (16.12)
|
0.846
|
0.680
|
Smoking history n (%)
|
61 (31.12)
|
11 (35.48)
|
236 (31.98)
|
81 (33.47)
|
0.554
|
0.777
|
Drinking history n (%)
|
39 (19.90)
|
6 (19.35)
|
145 (19.65)
|
47 (19.42)
|
0.917
|
0.995
|
Medication compliance
|
|
|
Regular medication n (%)
|
187 (95.41)
|
31 (100%)
|
705 (95.53)
|
231 (95.45)
|
0.551
|
0.961
|
BMI: Body Mass Index; PLT: Platelet Count; ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase; BUN: Blood Urea Nitrogen; CREA: Serum Creatinine.
3.2. Loss to Follow-up Situation
Figure 2 Loss to follow-up situation of the metabolic groups.
As shown in Figure 1 andFigure 2, the number of loss to follow-up cases in the normal metabolic group was 247 (53.70%), 164 (35.65%) in the intermediate metabolic group, and 49 (10.65%) in the poor metabolic group.
Among 2,403 selected patients, 460 patients were not included in the analysis due to reasons such as changing contact information and refusing to follow up, but 1,943 patients were enrolled.
There was a significant difference in the total loss to follow-up situation among patients in three metabolic groups (P < 0.001). We further conducted a comparison between the two metabolic groups and found that there were statistically significant differences mainly between the normal metabolic group and the intermediate metabolic group/poor metabolic group (P < 0.001/P < 0.001). While there was no loss to follow-up difference between the intermediate metabolic group and the poor metabolic group (P = 0.901) in Table 4. It can explained that the recommendations of the normal metabolic group did not change the dosage or type of clopidogrel taken by the patients. Therefore, the emphasis of patients from the normal metabolic group on the content of the study and follow-up was different from that of the intermediate and poor metabolic groups.
Table 4 Comparison of Loss to Follow-up Cases between Metabolic Groups
Metabolic Groups Comparison
|
p-value
|
Normal Metabolic
|
Intermediate Metabolic
|
<0.001
|
Normal Metabolic
|
Poor Metabolic
|
<0.001
|
Intermediate Metabolic
|
Poor Metabolic
|
0.901
|
3.3. Distribution of CYP2C19 Genotypes and Adoption of Clopidogrel Medication Recommendations
The distribution ratios of different detected CYP2C19 genotypes in ACS patients are different, which is shown in Table 5. Normal metabolizer type (*1/*1) accounts for 37.88% of the total number of cases included. Intermediate metabolizer type (*1/*2 and *1/*3) is detected more frequently, totaling 48.07%, among which *1/*2 is the main intermediate metabolizer type. While the Poor metabolizer type (*2/*2, *2/*3, and *3/*3) is 14.05% in total.
Table 5 The Distribution of CYP2C19 Metabolic Types
Metabolic type
|
Normal metabolizer
|
Intermediate metabolizer
|
Poor
metabolizer
|
Genotype
|
*1/*1
|
*1/*2
|
*1/*3
|
*2/*2
|
*2/*3
|
*3/*3
|
Number of genotype cases
|
736
|
804
|
130
|
193
|
72
|
8
|
Proportion of genotype
|
37.88%
|
41.38%
|
6.69%
|
9.93%
|
3.71%
|
0.41%
|
Number of cases
(adopted + unadopted)
|
/
|
174+630
|
22+108
|
20+173
|
11+61
|
0+8
|
Adoption proportion
|
/
|
21.64%
|
16.92%
|
10.36%
|
15.28%
|
0.00%
|
Total number of cases (n)
|
736
|
934
|
273
|
Adopted cases (n%)
|
/
|
196 (20.99)
|
31 (11.36)
|
Unadopted cases (n%)
|
/
|
738 (79.01)
|
242 (88.64)
|
It shows the adoption of clopidogrel medication recommendations based on CYP2C19 genotypes for enrolled patients (Table 5). For patients with the intermediate metabolic type, 20.99% adopted the medication recommendations, indicating that some doctors and patients are aware that the intermediate metabolic rate may affect the drug efficacy and thus made adjustments. However, 79.01% of the patients did not adopt the recommendations, possibly due to insufficient awareness of the impact of drug metabolism by physicians or patients, or their belief that the standard treatment plan is still effective.
Among Poor metabolizer-type patients, only 11.52% adopted the medication recommendations, and 88.64% did not adopt them. Since Poor metabolizer-type patients have a slower rate of metabolizing the drug and need to choose ticagrelor, the proportion of not adopting the recommendations is relatively high. This indicates that in clinical practice, both doctors and patients are still insufficiently aware of the influence of genotypes on drug metabolism. It is challenging for them to accept the recommendation to change the drug treatment plan. Some physicians also reported concerns that ticagrelor may relatively increase the risk of bleeding and it is difficult to balance the risk of ischemia and bleeding, so they did not accept the recommendation.
In conclusion, our data pointed out that the attention to the impact of CYP2C19 genotypes on clopidogrel metabolism and the actual adoption of medication adjustments still need to be improved in clinical practice. Future work should strengthen the publicity and education on the impact of Intermediate metabolizer type and Poor metabolizer type genotypes on drug efficacy, and promote the implementation of individualized medication plans guided by genotypes.
3.4. Relationship between Clopidogrel Metabolic Types- Adoption of Medication Recommendations and Incidence of Ischemic Events
Table 6 The Occurrence of Ischemic Events
Ischemic events/Group
|
Normal Metabolic
|
Intermediate Metabolic
|
Poor Metabolic
|
Total number of cases
|
p-value
|
Unstable angina pectoris
|
32 (4.35)
|
48 (5.14)
|
33 (12.09)
|
113 (5.82)
|
0.405
|
Non-fatal myocardial infarction
|
11 (1.49)
|
18 (1.93)
|
13 (4.76)
|
42 (2.16)
|
0.902
|
Cardiogenic and vascular death
|
6 (0.82)
|
9 (0.96)
|
6 (2.20)
|
21 (1.08)
|
0.843
|
In-stent stenosis/thrombosis
|
32 (4.35)
|
67 (7.17)
|
45 (16.48)
|
144 (7.41)
|
0.908
|
Revascularization
|
30 (4.08)
|
72 (7.71)
|
54 (19.78)
|
156 (8.03)
|
0.389
|
Total ischemic events
|
111 (15.08)
|
214 (22.91)
|
151 (55.31)
|
476 (24.50)
|
<0.001
|
In this study, we analyzed the data of different types of ischemic events in ACS patients with different CYP2C19 metabolic genotypes undergoing PCI, including unstable angina pectoris, nonfatal myocardial infarction, cardiogenic and vascular death, in-stent stenosis/thrombosis, and revascularization cases. We analyzed the occurrence of ischemic events in patients of the metabolic groups. It showed no significance was found in the occurrence of ischemic events among different metabolic groups, but there was a statistically significant difference in the total ischemic events (p < 0.001), and the incidence of each event increased as the metabolism slowed (Table 6).
Based on whether the medication recommendations were adopted or not, we conducted the intermediate metabolic group, the adoption of recommendations, and the occurrence of unstable angina pectoris, nonfatal myocardial infarction, cardiogenic and vascular death, in-stent stenosis/thrombosis, and revascularization, p > 0.05, with no statistically significant difference. However, there was a statistically significant difference in the total ischemic events, p = 0.041. Therefore, the results suggest that whether the recommendations are Adopted or not in the intermediate metabolic group may indicate that it does not affect the occurrence of specific ischemic events in the statistics but will increase the occurrence of total ischemic events. Adopting the recommendations can reduce the risk of total ischemic events by approximately 32.6% (Table 7).
Table 7 The Comparison of Ischemic Events in the Intermediate Metabolic Group
Group
|
Occurrence of
events
|
No occurrence of events
|
p-value
|
Odds ratio (OR)
|
Adopted situation
|
Adopted
|
Unadopted
|
Adopted
|
Unadopted
|
Unstable angina pectoris
|
10
|
38
|
186
|
700
|
0.979
|
0.990
|
Non-fatal myocardial infarction
|
3
|
15
|
193
|
723
|
0.650
|
0.749
|
Cardiogenic and vascular death
|
1
|
8
|
195
|
730
|
0.465
|
0.468
|
In-stent stenosis/thrombosis
|
9
|
58
|
187
|
680
|
0.115
|
0.564
|
Revascularization
|
10
|
62
|
186
|
676
|
0.124
|
0.586
|
Total ischemic events
|
33
|
181
|
947
|
3509
|
0.041
|
0.676
|
Table 8 The Comparison of Ischemic Events in the Poor Metabolic Group
Group
|
Occurrence of
events
|
No occurrence of events
|
p-value
|
Odds ratio (OR)
|
Adopted situation
|
Adopted
|
Unadopted
|
Adopted
|
Unadopted
|
Unstable angina pectoris
|
2
|
31
|
29
|
211
|
0.307
|
0.469
|
Non-fatal myocardial infarction
|
1
|
12
|
30
|
230
|
0.647
|
0.639
|
Cardiogenic and vascular death
|
1
|
5
|
30
|
237
|
0.678
|
1.580
|
In-stent stenosis/thrombosis
|
1
|
44
|
30
|
198
|
0.035
|
0.150
|
Revascularization
|
2
|
52
|
29
|
190
|
0.048
|
0.252
|
Total ischemic events
|
7
|
144
|
148
|
1066
|
0.006
|
0.350
|
For the poor metabolic group, the adoption of recommendations and the occurrence of unstable angina pectoris, non-fatal myocardial infarction, and cardiogenic and vascular death, p > 0.05, showing no statistically significant difference. However, it significantly affects in-stent stenosis/thrombosis (p= 0.035), revascularization (p= 0.048), and total ischemic events (p= 0.006). Therefore, the recommendations that are unadopted in the poor metabolic group may suggest an increased situation of in-stent stenosis/thrombosis and revascularization in ACS patients undergoing PCI, and not adopting the relevant opinions may increase the result of total ischemic events. Adopting the recommendations can reduce the risk of in-stent stenosis, thrombosis, revascularization, and total ischemic events by approximately 85.0%, 74.8%, and 65.0%, respectively (Table 8).
3.5. Relationship between the Adoption of Clopidogrel Metabolic Types- Medication Recommendations and the Incidence of Bleeding Events
Here we show the relationship between the adoption or unadoption of clopidogrel medication recommendations and the incidence of bleeding events (mild to moderate bleeding and fatal major bleeding) in patients of different CYP2C19 metabolic types (normal metabolic groups, intermediate metabolic groups, and poor metabolic Group) (Table 9). We include the number of cases of bleeding events in each group, the p-value, the total number of bleeding cases, and the odds ratio (OR) value. normal metabolic group: There were 43 cases of mild to moderate bleeding and 17 cases of fatal major bleeding.
Table 9 The Relationship between CYP2C19 Metabolic Types and Bleeding Events
Metabolic group
|
Normal metabolic
|
Abnormal metabolic
|
Total
|
Intermediate metabolic
|
Intermediate metabolic
|
Poor metabolic
|
Poor metabolic
|
Adopted situation
|
|
|
Adopted
|
Unadopted
|
Adopted
|
Unadopted
|
Mild to moderate bleeding
|
43
|
78
|
10
|
48
|
2
|
18
|
Fatal major bleeding
|
17
|
22
|
1
|
13
|
1
|
7
|
p-value
|
0.366
|
0.346
|
0.847
|
Total number of bleeding cases
|
|
|
11
|
61
|
3
|
25
|
Number of non-bleeding cases
|
|
|
185
|
611
|
28
|
217
|
p-value
|
|
|
0.122
|
0.910
|
Total number of bleeding cases odds ratio (OR)
|
|
|
0.60
|
0.93
|
In the intermediate metabolic group, among the adopted patients, there were 10 cases of mild to moderate bleeding and 1 case of fatal major bleeding, while among the unadopted patients, there were 48 cases and 7 cases, respectively. The results of the chi-square test showed that the p-value for mild to moderate bleeding and fatal major bleeding caused by adoption or not is 0.346, and there is no statistically significant difference in their occurrence (p > 0.05). The total number of bleeding and non-bleeding events in adopted and unadopted patients of the intermediate metabolic group indicates that the adoption of recommendations does not lead to the occurrence of bleeding events, with no statistically significant difference (p > 0.05). The odds ratio (OR) of the total number of bleeding cases is 0.60, suggesting that the adoption of medication recommendations in the intermediate metabolic group may slightly reduce the risk of bleeding, but it does not reach statistical significance.
In the poor metabolic group, there were 2 cases of mild to moderate bleeding, while among the unadopted patients, there were 18 cases of mild to moderate bleeding and 5 cases of fatal major bleeding. The p-value for mild to moderate bleeding and fatal major bleeding with or without adoption is 0.847, indicating no statistically significant difference in their occurrence (p > 0.05). The total number of bleeding and non-bleeding events in the adopted and unadopted groups of the poor metabolic group indicates that adoption does not lead to the occurrence of bleeding events, with no statistically significant difference (p > 0.05). The odds ratio (OR) of the total number of bleeding cases is 0.93, suggesting that the adoption of medication recommendations in the poor metabolic group may slightly reduce the risk of bleeding, but it does not reach statistical significance.
According to the results of bleeding events, it can be concluded that individualized guidance based on the CYP2C19 genotype for clopidogrel does not increase bleeding outcomes in patients with intermediate or poor metabolizers.