A real-world study of clopidogrel therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention guided by individualized metabolic types

doi:10.21203/rs.3.rs-4836948/v1

Purpose: To explore the relationship between adopting the recommendation for clopidogrel use based on genotype guidance in Acute Coronary Syndrome (ACS) patients undergoing Percutaneous Coronary Intervention (PCI) and the incidence of later cardiovascular ischemic and bleeding events.

Methods: A retrospective study was conducted on 3, 004 ACS patients treated with clopidogrel. Patients were grouped based on CYP2C19 genotype and followed for one year to record cardiovascular adverse and bleeding events.

Results: Adopting the recommendation for clopidogrel use can reduce the risk of total ischemic events in the intermediate metabolic group (Odds Ratio [OR], 0.676; P = 0.041). In the poor metabolic group, the recommendations could reduce the risk of in-stent stenosis/thrombosis (OR, 0.150; P = 0.035), revascularization (OR, 0.252; P = 0.048), and total ischemic events (OR, 0.350; P = 0.006). Individualized guidance based on the CYP2C19 genotype did not increase bleeding outcomes.

Conclusion:Individualized clopidogrel guidance based on genotype can reduce the ischemic risk in patients with intermediate and poor metabolizers, and the poor metabolic group benefits more. Individualized guidance did not increase bleeding outcomes in patients with intermediate or poor metabolizers.

Clopidogrel

CYP2C19 Genotype

Metabolic Types

Individualized medication

Acute Coronary Syndrome

Percutaneous Coronary Intervention

Acute Coronary Syndrome (ACS) is a cardiovascular disease that seriously threatens human health. Percutaneous Coronary Intervention (PCI) is one of the important methods of treatment^[1]. Clopidogrel, a commonly used antiplatelet drug, plays a key role in preventing thrombosis and reducing the risk of cardiovascular events^[2]. Clopidogrel is a prodrug that is mediated by P-glycoprotein during intestinal absorption. A portion of it is metabolized by the cytochrome CYP 450 enzyme system in the liver into an active metabolite, which selectively and irreversibly inhibits the adenosine diphosphate (ADP) receptor (P2Y12), thereby preventing platelet aggregation ^[3]. However, only about 15% of clopidogrel is converted into an active form in the liver, and the remaining 85% is hydrolyzed by esterase and loses its activity ^[4].

Clopidogrel is mainly used to treat patients with ACS and after PCI, and can reduce the mortality rate and other cardiovascular events in ACS patients without revascularization ^[5]. However, studies have found that after using clopidogrel, there are a variety of poor prognosis situations such as myocardial infarction, stent thrombosis, ischemic stroke, and revascularization ^[6]. The risk of poor prognosis situations varies among individuals, and the influencing factors mainly include race, age, genetic polymorphism, drug interactions, and patient compliance ^[7].

Among these, the genetic polymorphism of CYP2C19 plays a key role in the metabolism of clopidogrel ^[8]. Patients carrying the CYP2C192 and CYP2C193 genes have lower sensitivity to clopidogrel, and their antiplatelet effect is not as pronounced as that of wild-type gene patients, which may lead to the occurrence of cardiovascular clinical events ^[9].

In recent years, there have been continuous studies on the relationship between the CYP2C19 genotype and the efficacy of clopidogrel. Some studies have shown that the genetic polymorphism of CYP2C19 is related to clopidogrel resistance, which is a high-risk factor for adverse cardiovascular events ^{[10, 11]}.

However, meta-analyses have also reported a lack of effect of CYP2C19 no-function alleles on adverse cardiovascular outcomes among patients receiving clopidogrel for non-PCI cardiovascular indications, possibly due to lower clinical benefit from treatment with clopidogrel in these patient populations ^[12]. In addition to the CYP2C19 gene, the polymorphisms of other genes such as ABCB1, CES1, CYP1A2, CYP2B6, CYP3A4, CYP3A5, and CYP2C9, as well as drug interactions, patients' comorbidities, physiological conditions at different ages, living habits, and patient compliance, may also affect the efficacy of clopidogrel^{[13, 14]}.

Taken together, this study aims to explore the relationship between the adoption of clopidogrel medication recommendations based on genotype guidance in ACS patients undergoing PCI (especially in patients with intermediate metabolic genotypes) and the incidence of later cardiovascular ischemic and bleeding events, to provide a reference for clinical rational use of drugs.

2.1 General Information

Table 1 Individualized advice based on the CYP2C19 genotype of clopidogrel

Gene	Phenotype	Diplotypes	Individualized advice
CYP2C19	Normal metabolizer	1/1	Use the standard dose of clopidogrel 75mg qd
	Intermediate metabolizer	1/2	It is recommended to increase the platelet function test ADP (LTA method) to determine the efficacy. ≥ 30% use the standard dose of 75mg. < 30% It is recommended to increase the dosage of clopidogrel to 150mg/d or switch to other antiplatelet drugs such as ticagrelor.
	Intermediate metabolizer	1/3
	Poor metabolizer	2/2	It is recommended to switch to ticagrelor

In our retrospective study, the 3,004 patients diagnosed with ACS and treated with clopidogrel were selected and admitted to Guangdong Provincial People's Hospital (Guangzhou, China) from January 2016 to March 2024, using the following inclusion criteria diagnosed with coronary atherosclerotic heart disease (including ischemic cardiomyopathy, angina pectoris, and myocardial infarction) by coronary arteriography (coronary arteriography, CAG). The patients/subjects received the advice for clopidogrel medication proposed by clinical pharmacists based on the results of CYP2C19 genotyping. The advice for clopidogrel medication is shown in Table 1.

Normal metabolizers only had the effect of studying the differences between metabolic groups and were not grouped into the adopted group or the unadopted group, due to unchanged recommended standard dosage of clopidogrel and without other advice given. The exclusion criteria are listed below:

1. Patients who have contraindications to clopidogrel or do not take clopidogrel

2. Patients with incomplete medical records

3. Patients with a previous history of ischemic or hemorrhagic diseases, hematological diseases or bleeding diathesis, and platelet count > 450×10^9 or < 100×10^9

4. Patients with combined malignant diseases such as tumors

5. Patients with severe liver or kidney diseases, coagulation disorders, or anemia [hemoglobin (Hb) level < 100g/L]

6. Non-Han population

2.2 Methods

2.2.1 Data Collection

The complete clinical data of the selected patients was reviewed through the hospital's electronic medical recording system:

General conditions: gender, age, height, weight, and body mass index (BMI).
Risk factors of ACS: hypertension, diabetes, hyperlipidemia, smoking, and drinking.
Coronary intervention conditions: the number of stent implants.
Laboratory test results: platelet count, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and serum creatinine.
Drug compliance score MORISKY score (Definition: MORISKY score ≥ 6, that is, good and moderate compliance, belongs to regular medication).

2.2.2 Grouping of Research Subjects

According to the genotyping results of the CYP2C19, patients were divided into the normal metabolism group and the abnormal metabolism group. The abnormal metabolism group was further divided into the intermediate metabolism group and the poor metabolism group. The grouping was mainly distinguished based on the different metabolic capabilities of CYP2C19. Normal metabolizer type is with the genotype of CYP2C19*1/*1. Intermediate metabolizer type is CYP2C19*1/*2 or CYP2C19*1/*3. The poor metabolizer type is CYP2C19*2/*2, CYP2C19*2/*3, or CYP2C19*3/*3.

2.2.3 Clinical Follow-up

A follow-up plan was formulated to obtain the data of the follow-up patients. The selected patients were followed up by rehospitalization or telephone calls to understand and record the occurrence of various cardiovascular adverse events and bleeding events within one year of taking clopidogrel.

Cardiovascular adverse events include cardiogenic death, non-fatal myocardial infarction, unstable angina pectoris, in-stent stenosis or thrombosis, and subsequent revascularization.

Bleeding events include mild to moderate bleeding events like gingival bleeding, subcutaneous ecchymosis, epistaxis, conjunctival hemorrhage, gross hematuria, and fatal major bleeding including intracranial hemorrhage, gastrointestinal bleeding, and so on.

The definitions of cardiovascular adverse events are as follows:

Cardiogenic death: Any definite death due to cardiovascular causes or death that is not attributed to non-cardiovascular causes.
Non-fatal myocardial infarction: New ischemic symptoms occur, the ST segment of the electrocardiogram is significantly depressed or elevated, and troponin is significantly increased.
Unstable angina pectoris: It occurs at rest and lasts for more than 20 minutes, or the degree of angina pectoris is more severe, lasts longer, or is more frequent than before, and is confirmed by myocardial enzymes or electrocardiogram.

2.2.4 Statistical Methods

Data processing was performed using SPSS 27.0 statistical software. Measurement data that obeyed a normal distribution or approximately normal distribution were expressed as the mean ± standard deviation (x ± s). The t-test was used for the comparison of means between two groups, and one-way analysis of variance (ANOVA) was used for the comparison of means among multiple groups.

Measurement data that did not follow a normal distribution were expressed as the median (interquartile range), and non-parametric tests were used for comparison between groups. Count data were expressed as frequency/ percentage, and the chi-square test was used for comparison between groups. p < 0.05 indicated a statistically significant difference.

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)	0.654
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
Item/ group	Intermediate Metabolic^a(n=196)	Poor Metabolic^b(n=31)	Intermediate Metabolic^c(n=738)	Poor Metabolic^d (n=242)	p-value
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)	0.391	0.878
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	p-value	Odds ratio (OR)
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	p-value	Odds ratio (OR)
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
Metabolic group	Normal 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.

4.1. Disadvantages of this study

This study is a single-center sample with a small number of follow-up visits, which may make it difficult to predict the overall situation.
The loss to follow-up rate is high, and the analysis results may be biased.
The individualized use of clopidogrel is mainly recommended for ACS patients undergoing PCI. However, a small number of patients who planned to undergo PCI canceled the procedure for some reasons, which may have a certain impact on the results.
The situation of patients taking other drugs in combination is not clear, and drug interactions may have a certain impact on the results.

4.2. Analysis of the research results

Through the statistical analysis of ACS patients with different CYP2C19 metabolic genotypes, it is found that there is no difference in the occurrence of ischemic events among different metabolic groups, but there is a statistically significant difference in the total ischemic events, and the incidence of each event increases as the metabolism slows down.

For the intermediate metabolic group, whether the recommendation is adopted or not has no statistically significant impact on the occurrence of specific ischemic events, but it will increase the occurrence of total ischemic events. Adopting the recommendation can reduce the risk of total ischemic events by approximately 32.6%. For the poor metabolic group, whether the recommendation is adopted or not has no statistically significant impact on the occurrence of unstable angina pectoris, non-fatal myocardial infarction, and cardiogenic and vascular death, but it has an impact on in-stent stenosis/thrombosis, revascularization, and total ischemic events, with statistically significant differences. Adopting the recommendation can reduce the risk of in-stent stenosis/thrombosis, revascularization, and total ischemic events by approximately 85.0%, 74.8%, and 65.0%, respectively.

Based on the results of bleeding events, it can be concluded that the individualized guidance suggestions based on the CYP2C19 genotype of clopidogrel do not increase the bleeding outcomes in patients with intermediate metabolizers or poor metabolizers.

4.3. Implications for clinical practice

These data reflect that in clinical practice, the attention to the impact of CYP2C19 genotypes on clopidogrel metabolism and the actual adoption of medication adjustments still need to be improved.

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.

In conclusion, this study guides the clinical rational use of drugs, but further expansion of the sample size and improvement of the research design still need to evaluate more accurately the role of genotype-guided clopidogrel antiplatelet therapy in ACS patients undergoing PCI.

This real-world study investigated the relationship between the adoption of clopidogrel medication recommendations based on genotype guidance in ACS patients undergoing PCI and the incidence of later cardiovascular ischemic and bleeding events. The main findings are as follows:

In the intermediate metabolic group, adopting the clopidogrel medication recommendation can reduce the risk of total ischemic events by approximately 32.6%.
In the poor metabolic group, adopting the recommendation can reduce the risk of in-stent stenosis/thrombosis, revascularization, and total ischemic events by approximately 85.0%, 74.8%, and 65.0%, respectively.
Individualized guidance based on the CYP2C19 genotype for clopidogrel did not increase bleeding outcomes in patients with intermediate or poor metabolizers.

This study highlights the importance of considering CYP2C19 genotypes in clopidogrel therapy. However, it also has several limitations, including being a single-center sample with a small number of follow-up visits, a high loss to follow-up rate, and uncertainties regarding patients taking other drugs. Future work should expand the sample size, improve the research design, and strengthen publicity and education on the impact of genotype-guided individualized medication plans to better evaluate the role of genotype-guided clopidogrel antiplatelet therapy in ACS patients undergoing PCI.

Author Contributions

Yanpeng Li and Zhilei Li are co-first authors and contributed equally to this work.

All authors contributed to the study's conception and design. Clinical data review was primarily performed by Zhilei Li, Haodong Cui, and Huan Dong, with additional contributions from Zhilei Li, Dongmei He, and Ziyuan Zhou. Data processing and statistical analysis were mainly conducted by Zhilei Li and Yanpeng Li. The first draft of the manuscript was written by Zhilei Li and Yanpeng Li, and subsequent editing and proofreading of the article manuscript were carried out by Yanpeng Li, Xiujuan Yang, and Xiaojuan Zhang. All authors provided valuable comments on previous versions of the manuscript, and all read and approved the final manuscript.

Funding

This paper is funded by the outstanding young fund project for district-university cooperation in major projects of the health system in Nanshan district, Shenzhen (NSZD2023062)and the National Natural Science Foundation of China (No.82073805).

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code Availability

Not applicable.

Ethics approval

This study was approved by the Ethics Committee of Guangdong Provincial People's Hospital. The ethics approval number is KY2024-5 14-01. The study was conducted by the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Consent for participate

This study was exempted from the informed consent process as approved by the Ethics Committee of Guangdong Provincial People's Hospital. The research has de-identified information of identifiable individuals, removing personal and private information such as names, addresses, and occupations. This has no impact on the research content.

Consent for Publication

The authors affirm that human research participants provided informed consent for the publication of the images in Figure 1-2, Table1-9, These contents are only used for scientific research and statistics and do not involve the personal privacy of the participating patients.

Conflicts of Interest

The authors have no relevant financial or non-financial interests to disclose.

Cavallari LH, Lee CR, Beitelshees AL, Cooper-DeHoff RM, Duarte JD, Voora D, et al. Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention. JACC Cardiovasc Interv. 2018 Jan 22;11 (2):181-191. doi: 10.1016/j.jcin.2017.07.022. Epub 2017 Nov 1. PMID: 29102571; PMCID: PMC5775044.
Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, et al. Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013 Sep;94 (3):317-23. doi: 10.1038/clpt.2013.105. Epub 2013 May 22. PMID: 23698643; PMCID: PMC3748366.
Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010 Jan;38 (1):92-9. doi: 10.1124/dmd.109.029132. PMID: 19812348.
Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009 Aug 26;302 (8):849-57. doi: 10.1001/jama.2009.1232. PMID: 19706858; PMCID: PMC3641569.
Pereira NL, Farkouh ME, So D, Lennon R, Geller N, Mathew V, et al. Effect of Genotype-Guided Oral P2Y12 Inhibitor Selection vs Conventional Clopidogrel Therapy on Ischemic Outcomes After Percutaneous Coronary Intervention: The TAILOR-PCI Randomized Clinical Trial. JAMA. 2020 Aug 25;324 (8):761-771. doi: 10.1001/jama.2020.12443. PMID: 32840598; PMCID: PMC7448831.
Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010 Oct 27;304 (16):1821-30. doi: 10.1001/jama.2010.1543. PMID: 20978260; PMCID: PMC3048820.
Verma SS, Bergmeijer TO, Gong L, Reny JL, Lewis JP, Mitchell BD, Alexopoulos D, et al. Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium. Clin Pharmacol Ther. 2020 Nov;108 (5):1067-1077. doi: 10.1002/cpt.1911. Epub 2020 Jul 9. PMID: 32472697; PMCID: PMC7689744.
Sibbing D, Gebhard D, Koch W, Braun S, Stegherr J, Morath T, et al. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. J Thromb Haemost. 2010 Aug;8 (8):1685-93. doi: 10.1111/j.1538-7836.2010.03921.x. Epub 2010 May 21. PMID: 20492469.
Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation. 2010 Feb 2;121 (4):512-8. doi: 10.1161/CIRCULATIONAHA.109.885194. Epub 2010 Jan 18. PMID: 20083681.
Pan Y, Chen W, Xu Y, Yi X, Han Y, Yang Q, et al. Genetic Polymorphisms and Clopidogrel Efficacy for Acute Ischemic Stroke or Transient Ischemic Attack: A Systematic Review and Meta-Analysis. Circulation. 2017 Jan 3;135 (1):21-33. doi: 10.1161/CIRCULATIONAHA.116.024913. Epub 2016 Nov 2. PMID: 27806998.
Collet JP, Thiele H, Barbato E, Barthélémy O, Bauersachs J, Bhatt DL, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2021 Apr 7;42 (14):1289-1367. doi: 10.1093/eurheartj/ehaa575. PMID: 32860058.
Sorich MJ, Rowland A, McKinnon RA, Wiese MD. CYP2C19 genotype has a greater effect on adverse cardiovascular outcomes following percutaneous coronary intervention and in Asian populations treated with clopidogrel: a meta-analysis. Circ Cardiovasc Genet. 2014 Dec;7 (6):895-902. doi: 10.1161/CIRCGENETICS.114.000669. Epub 2014 Sep 25. PMID: 25258374.
Botton MR, Whirl-Carrillo M, Del Tredici AL, Sangkuhl K, Cavallari LH, Agúndez JAG, et al. PharmVar GeneFocus: CYP2C19. Clin Pharmacol Ther. 2021 Feb;109 (2):352-366. doi: 10.1002/cpt.1973. Epub 2020 Jul 22. PMID: 32602114; PMCID: PMC7769975.
Angiolillo DJ, Capodanno D, Danchin N, Simon T, Bergmeijer TO, Ten Berg JM, et al. Derivation, Validation, and Prognostic Utility of a Prediction Rule for Nonresponse to Clopidogrel: The ABCD-GENE Score. JACC Cardiovasc Interv. 2020 Mar 9;13 (5):606-617. doi: 10.1016/j.jcin.2020.01.226. PMID: 32139218.

A real-world study of clopidogrel therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention guided by individualized metabolic types

Status:

Version 1

Abstract

Figures

1. Introduction

2. Materials and Methods