Clopidogrel Use in CYP2C19 Loss-of-Function Carriers With High Bleeding Risk After Percutaneous Coronary Intervention

Abstract

Background: It is not known whether clopidogrel use in cytochrome P450 (CYP) 2C19 loss-of-function (LOF) carriers with high bleeding risk (HBR) contributes to adverse outcomes after percutaneous coronary intervention (PCI).

Methods and Results: This retrospective observational study included 618 consecutive patients with available CYP2C19 polymorphism information who underwent PCI between September 2014 and August 2021. Patients with HBR (319 [52%] met the Academic Research Consortium definition) were divided into 2 groups according to P2Y₁₂ inhibitor action, namely decreased (i.e., clopidogrel in CYP2C19 LOF carriers) and retained (i.e., clopidogrel in CYP2C19 LOF non-carriers or prasugrel regardless of CYP2C19 polymorphisms), and clinical outcomes at 1 year were compared using inverse probability-weighted Cox proportional hazard regression. The primary ischemic outcome (a composite of cardiovascular death, myocardial infarction, or ischemic stroke) was significantly higher in the decreased than retained group (10.2% vs. 3.0%; adjusted hazard ratio [aHR] 2.78; 95% confidence interval [CI] 1.40–5.52; P=0.004). The primary bleeding outcome (Bleeding Academic Research Consortium 3 or 5) did not differ significantly between the decreased and retained groups (3.4% vs. 6.9%, respectively; aHR 0.48; 95% CI 0.22–1.01; P=0.054). There were no interactions between the treatment groups and HBR status in primary ischemic and bleeding outcomes.

Conclusions: Among patients with HBR, clopidogrel use in CYP2C19 LOF carriers was significantly associated with increased ischemic events after PCI.

A P2Y₁₂ inhibitor (P2Y₁₂-I) in addition to aspirin is the cornerstone of treatment to reduce subsequent ischemic events in patients undergoing percutaneous coronary intervention (PCI). Clopidogrel, a conventional P2Y₁₂-I, is a prodrug that undergoes metabolic transformation in the liver by cytochrome P450 (CYP) 2C19 to elicit its antiplatelet effect. A CYP2C19 loss-of-function (LOF) allele leads to a lower plasma concentration of the active clopidogrel metabolite, resulting in reduced inhibition of platelet aggregation.¹ Randomized control trials^2,3 and a meta-analysis⁴ have shown that treatment with clopidogrel in CYP2C19 LOF carriers results in an increase in ischemic events after PCI compared with those treated with drugs that are less susceptible to CYP2C19, including prasugrel or ticagrelor. In this context, the US Food and Drug Administration has suggested an alternative P2Y₁₂-I to clopidogrel for patients who are CYP2C19 poor metabolizers.⁵

Recently, some populations receiving PCI have comprised patients with high bleeding risk (HBR). The Academic Research Consortium for High Bleeding Risk (ARC-HBR) has standardized the definition of HBR, which is arbitrarily defined as Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding greater than 4% at 1 year after PCI.⁶ Previous registries have shown that patients with HBR have an approximately 3-fold higher rate of bleeding events after PCI than those without HBR.^7–9 Accordingly, for patients with HBR, physicians may be hesitant to prescribe potent P2Y₁₂-I, such as prasugrel or ticagrelor, because of their potential to increase bleeding risk.^10,11 Instead, clopidogrel may be preferred. In addition, current European Society of Cardiology guidelines recommend clopidogrel as a component of dual antiplatelet therapy (DAPT) for patients with HBR after PCI, even in the setting of acute coronary syndrome (ACS).¹² However, evidence is still lacking as to whether it is acceptable to prescribe clopidogrel to patients with HBR, even if they are CYP2C19 LOF carriers. This is an essential topic in clinical practice because patients with HBR also have a simultaneously high risk of ischemic events.^7–9,13,14

Therefore, in the present study, we assessed whether clopidogrel use in CYP2C19 LOF carriers contributes to adverse outcomes among patients with HBR who undergo PCI. We also examined whether the association between clopidogrel use in CYP2C19 LOF carriers and clinical outcomes differs by the presence or absence of HBR.

Methods

Data Source and Study Population

This study was a retrospective observational study of consecutive patients who underwent PCI and who had their CYP2C19 variants assessed at Shiga University of Medical Science Hospital between September 2014 and August 2021.¹⁵CYP2C19 variants are determined in routine clinical practice when drugs that could be metabolized by CYP2C19, such as P2Y₁₂-I or proton pump inhibitors, are used. In the present study, patients were regarded as having HBR when they satisfied at least 1 major and/or 2 minor ARC-HBR criteria.⁶

We screened patients treated with P2Y₁₂-I after implantation of a second- or third-generation drug-eluting stent. Patients who could not be followed for more than 1 year for reasons other than death (e.g., referral to other hospitals) were excluded. Then, among patients with HBR, we evaluated clinical events at 1 year between those with decreased P2Y₁₂-I action (i.e., use of clopidogrel in CYP2C19 LOF carriers) and those with retained P2Y₁₂-I action (i.e., use of clopidogrel in CYP2C19 LOF non-carriers or the use of prasugrel/ticagrelor regardless of CYP2C19 polymorphisms). Previous studies have shown that both clopidogrel and prasugrel are expected to be equally effective in preventing thrombotic events in CYP2C19 LOF non-carriers.^3,10,15 In addition, prasugrel can prevent ischemic events after PCI without being affected by CYP2C19 LOF carrier or non-carrier status.¹⁶ Therefore, we merged these populations (CYP2C19 LOF non-carriers prescribed clopidogrel and CYP2C19 LOF carriers and non-carriers prescribed prasugrel) as the group with retained P2Y₁₂-I action and compared them to the group with decreased P2Y₁₂-I action.

This study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice, and was approved by the Shiga University of Medical Science Research Ethics Committee (Reference no. R2019-193). Consent was obtained from all participants in the study using an opt-out procedure.

Assessment of CYP2C19 Polymorphisms

CYP2C19 genotyping was performed using an Applied Biosystems StepOnePlus real-time polymerase chain reaction system. CYP2C19 variants were classified according to the following genotypes: *1 (wild type), *2 (681G>A [rs4244285]), *3 (636G>A [rs4986893]), and *17 (-806C>T [rs12248560]). Genotypes *2 and *3 are considered LOF alleles that decrease enzyme action, whereas genotype *17 increases enzyme action. CYP2C19 polymorphisms were determined by the combination of variants as follows: (1) normal metabolizer (*1/*1); (2) intermediate metabolizer (*1/*2, *1/*3); (3) poor metabolizer (*2/*2, *2/*3, *3/*3); (4) rapid metabolizer (*1/*17); and (5) other (*2/*13, *3/*17).¹⁷ We classified poor metabolizer and intermediate metabolizer patients as CYP2C19 LOF carriers, and normal metabolizer and rapid metabolizer patients as CYP2C19 LOF non-carriers. The group “other” (*2/*13, *3/*17) was not included in this analysis because enzyme action in this group was unknown.

Study Outcomes

As a primary outcome, in accordance with the trial design principles for patients with HBR undergoing PCI,¹⁸ the ischemic outcome was defined as a composite of cardiovascular death (CVD), myocardial infarction (MI), or ischemic stroke within 1 year after the index PCI. The bleeding outcome was BARC¹⁹ type 3 or 5 bleeding within 1 year after the index PCI. As a secondary outcome, we assessed the following clinical outcomes within 1 year after the index PCI: any cause of death, definite stent thrombosis, clinically driven revascularization, component of the primary ischemic outcome, and BARC type 2, 3, or 5 bleeding. CVD was defined as cardiac death caused by coronary artery disease, stroke, or heart failure. MI was defined according to the 4th universal definition of MI.²⁰ Stent thrombosis was defined according to Academic Research Consortium criteria.²¹ Clinically driven revascularization was defined as treatment for recurrent angina in the presence of signs or symptoms of myocardial ischemia, regardless of PCI or coronary artery bypass grafting. Ischemic stroke was defined as acute spontaneous neurological deficit and was confirmed by magnetic resonance imaging.

Statistical Analysis

First, we assessed patient characteristics and compared them between patients with and without HBR. Categorical data are reported as numbers and percentages and were compared using the Chi-squared test or Fisher’s exact test. Continuous data are reported as the mean±SD or as the median and interquartile range (IQR) depending on the distribution of the data, and were compared using Student’s t-test and the Mann-Whitney U test, respectively. Next, among patients with HBR, we compared patient characteristics between those with decreased and retained P2Y₁₂-I action. To reduce the effect of treatment selection bias and potential confounding in this observational study,²² the propensity score was calculated using multivariable logistic regression analysis, which included the following variables: age, sex, body mass index, hypertension, diabetes, current smoking, dyslipidemia, peripheral vascular disease, prior MI, prior PCI, prior coronary artery bypass grafting, the components of ARC-HBR major criteria (i.e., moderate/severe anemia, oral anticoagulation, severe/end-stage chronic kidney disease, thrombocytopenia, surgery or trauma within 30 days, non-deferrable major surgery on DAPT, prior intracerebral hemorrhage or ischemic stroke, prior bleeding, bleeding diathesis, liver cirrhosis), the components of ARC-HBR minor criteria (i.e., mild anemia, moderate chronic kidney disease, prior ischemic stroke, non-steroidal anti-inflammatory drug or steroid use, prior bleeding), indication of PCI for ACS, target vessel, total stent length, number of stents, aspirin use, statin use, β-blocker use, angiotensin-converting enzyme inhibitor use, angiotensin II receptor blocker use, and DAPT duration. Then, the inverse probability weighting (IPW) method was used for a fair comparison between the 2 groups. Survival curves for the 2 groups were created using IPW-adjusted Kaplan-Meier plots, and IPW-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were calculated with the Cox proportional hazard regression model. In addition, we constructed the same multivariable logistic regression model among all patients (including patients both with and without HBR), and aligned patient backgrounds in the decreased and retained P2Y₁₂-I action groups. Then, IPW-adjusted HR and 95% CI were calculated using the Cox proportional hazards regression model, with interaction testing to assess the effect of the treatment groups and HBR status on the clinical outcomes. All reported P values are 2-sided, and P<0.05 was considered statistically significant. All data were analyzed using SAS version 9.4 (SAS Institute, Cary, NC, USA) and JMP version 16 (SAS Institute).

Results

Patient Characteristics

Of 732 patients who underwent PCI and who had CYP2C19 genotyping data available, 618 were analyzed in the present study (Figure 1). The study population consisted of middle-aged and older patients (mean age 69.8 years), and 78% of patients were male. In all, 66% of patients were CYP2C19 LOF carriers (intermediate metabolizers, 48%; poor metabolizers, 18%), and patients who underwent PCI for ACS accounted for 43% of the population (Supplementary Table 1). All patients received a maintenance dose of clopidogrel (75 mg/day) or prasugrel (3.75 mg/day). No patient received ticagrelor as a P2Y₁₂-I. Almost half the patients (n=319 [52%]) met the ARC-HBR criteria. Compared with patient without HBR, patients with HBR were older; more likely to be female; more often had diabetes, peripheral vascular disease, prior PCI, or chronic coronary syndrome as an indication for PCI; and had a subsequent shorter DAPT duration after PCI (Supplementary Table 1).

Figure 1.

Study flowchart. CYP2C19, cytochrome P450 2C19; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; HBR, high bleeding risk; LOF, loss of function; PCI, percutaneous coronary intervention.

Patient Characteristics by Treatment Group Among Patients With HBR

The characteristics of patients in the decreased and retained P2Y₁₂-I action groups among those with HBR are presented in Table 1. Although the clinical background factors were generally similar in both treatment groups, patients in the decreased P2Y₁₂-I action group more often had peripheral vascular disease and mild anemia than patients in the retained P2Y₁₂-I action group. Conversely, the presence of ST-segment elevation MI for the indication of PCI was significantly higher in the retained P2Y₁₂-I action group. Approximately 20% of patients in both groups had discontinued DAPT within 6 months. Within 1 year after index PCI, of the 88 patients in the decreased P2Y₁₂-I action group, 28 were converted to single antiplatelet therapy (aspirin, n=12; P2Y₁₂-I, n=16). In comparison, of 231 patients in the retained P2Y₁₂-I action group, 112 were converted to single antiplatelet therapy (aspirin, n=54; P2Y₁₂-I, n=58).

Table 1. Patient Characteristics by Treatment Group in Patients With HBR

	P2Y12-I action		P value
	Decreased (n=88)	Retained (n=231)
Clinical characteristics
Age (years)	75.4±8.6	73.8±9.5	0.170
Male sex	69 (78)	167 (72)	0.266
Body mass index (kg/m2)	23.5±3.5	23.1±3.6	0.302
Current smoker	13 (15)	37 (16)	0.785
Hypertension	77 (88)	183 (79)	0.089
Diabetes	39 (44)	105 (45)	0.856
Dyslipidemia	69 (78)	164 (71)	0.182
Peripheral vascular disease	33 (38)	47 (20)	0.002
Prior MI	11 (13)	27 (12)	0.842
Prior PCI	19 (22)	30 (13)	0.057
Prior CABG	5 (6)	8 (3)	0.357
CYP2C19 polymorphism			<0.001
Normal metabolizer	0 (0)	108 (47)
Intermediate metabolizer	65 (74)	87 (38)
Poor metabolizer	23 (26)	35 (15)
Rapid metabolizer	0 (0)	1 (0.4)
ARC-HBR
Major criteria
Oral anticoagulation	20 (23)	56 (24)	0.777
Moderate/severe anemia	20 (23)	48 (21)	0.704
Severe/end-stage CKD (eGFR <30 mL/min/1.73 m2)	15 (17)	29 (13)	0.299
Prior ischemic stroke or ICH	4 (5)	12 (5)	0.812
Non-deferrable major surgery on DAPT	4 (5)	8 (3)	0.743
Bleeding diathesis	3 (3)	2 (0.9)	0.131
Malignancy	2 (2)	13 (6)	0.252
Thrombocytopenia	2 (2)	9 (4)	0.734
Surgery or trauma within 30 days	1 (1)	3 (1)	0.907
Liver cirrhosis	1 (1)	0 (0)	–
Prior bleeding	0 (0)	1 (0.4)	–
Minor criteria
Age ≥75 years	53 (60)	129 (56)	0.480
Moderate CKD (eGFR 30–59 mL/min/1.73 m2)	46 (52)	122 (53)	0.931
Mild anemia	43 (49)	74 (32)	0.005
Prior ischemic stroke	13 (15)	27 (12)	0.457
NSAIDs or steroid use	7 (8)	24 (10)	0.512
Prior bleeding	0 (0)	1 (0.4)	–
Procedural characteristics
Indication of index PCI
ACS	22 (25)	97 (42)	0.005
STEMI	11 (13)	61 (26)	0.008
NSTEMI	5 (6)	25 (11)	0.160
UAP	6 (7)	11 (5)	0.577
CCS	66 (75)	134 (58)	0.005
Target vessel
Unprotected LMCA	9 (10)	15 (6)	0.259
LAD	62 (70)	149 (65)	0.315
LCX	20 (23)	47 (20)	0.641
RCA	28 (32)	92 (40)	0.187
No. stents	1 [1–2]	1 [1–2]	0.618
Total stent length (mm)	34 [22–53]	30 [22–53]	0.640
Medication at hospital discharge
Aspirin	85 (97)	230 (99)	0.033
Clopidogrel	88 (100)	52 (23)	<0.001
Prasugrel	0 (0)	179 (77)	–
Statin	75 (85)	209 (90)	0.180
β-blockers	37 (42)	102 (44)	0.734
ACE-I/ARB	51 (58)	155 (67)	0.127
DAPT duration after index PCI
DAPT duration within 1 year (days)	365 [215–365]	365 [200–365]	0.047
DAPT duration <6 months	16 (18)	49 (21)	0.548

Categorical data are reported as n (%) and were compared using the Chi-squared test or Fisher’s exact test. Continuous data are reported as the mean±SD or median [interquartile range] and were compared using the Student’s t-test and Mann-Whitney U test, respectively. ACE-I, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; ARB, angiotensin II receptor blocker; ARC, Academic Research Consortium; CABG, coronary artery bypass grafting; CCS, chronic coronary syndrome; CKD, chronic kidney disease; CYP2C19, cytochrome P450 2C19; DAPT, dual antiplatelet therapy; eGFR, estimated glomerular filtration rate; HBR, high bleeding risk; ICH, intracerebral hemorrhage; LAD, left anterior descending artery; LCX, left circumflex artery; LMCA, left main coronary artery; MI, myocardial infarction; NSAID, non-steroidal anti-inflammatory drug; NSTEMI, non-ST-segment elevation myocardial infarction; P2Y₁₂-I, P2Y₁₂ inhibitor; PCI, percutaneous coronary intervention; RCA, right coronary artery; STEMI, ST-segment elevation myocardial infarction; UAP, unstable angina pectoris.

One-Year Clinical Outcomes

Table 2 summarizes the event rates of the clinical outcomes in patients with HBR. Of 319 patients with HBR, 16 (5.0%) developed the primary ischemic outcome, and 19 (6.0%) developed the primary bleeding outcome. The decreased P2Y₁₂-I action group had a higher incidence of the primary ischemic outcome (10.2% vs. 3.0%) and a lower incidence of the primary bleeding outcome (3.4% vs. 6.9%) than the retained P2Y₁₂-I action group. Figure 2 shows the adjusted Kaplan-Meier curves of the primary ischemic and bleeding outcomes between the treatment groups (differences in patient characteristics after IPW adjustment are presented in Supplementary Table 2; unadjusted Kaplan-Meier curves are presented in the Supplementary Figure). After IPW adjustment, the cumulative incidence of the primary ischemic outcome was 9.6% in the decreased P2Y₁₂-I action group, which was significantly higher than in the retained P2Y₁₂-I action group (3.5%; adjusted HR [aHR] 2.78; 95% CI 1.40–5.52; P=0.004). The IPW-adjusted cumulative incidence of the primary bleeding outcome was numerically lower in the decreased than retained P2Y₁₂-I action group (3.3% vs. 6.9%, respectively; aHR 0.48; 95% CI 0.22–1.01; P=0.054). MI occurred more frequently in the decreased than retained P2Y₁₂-I action group (adjusted event rate 5.9% vs. 0.8%, respectively; aHR 7.52; 95% CI 2.05–27.6). There were no significant interactions between the treatment group and HBR status in the primary outcomes (primary ischemic outcome, P for interaction=0.780; primary bleeding outcome, P for interaction=0.219; Table 3). No interactions between treatment groups and HBR status were observed for each component of the secondary outcomes.

Table 2. Clinical Outcomes at 1 Year in Patients With HBR

	Crude event rates (%)		After IPW adjustment
	Decreased P2Y12-I action	Retained P2Y12-I action	Adjusted event rates (%)		HR (95% CI)	P value
			Decreased P2Y12-I action	Retained P2Y12-I action
Primary ischemic outcome
CVD/MI/ischemic stroke	9/88 (10.2)	7/231 (3.0)	9.6	3.5	2.78 (1.40–5.52)	0.004
Primary bleeding outcome
Bleeding (BARC 3 or 5)	3/88 (3.4)	16/231 (6.9)	3.3	6.9	0.48 (0.22–1.01)	0.054
Secondary outcomes
Any-cause death	5/88 (5.7)	10/231 (4.3)	6.7	4.2	1.64 (0.82–3.27)
CVD	4/88 (4.5)	4/231 (1.7)	4.1	1.9	2.20 (0.83–5.87)
MI	5/88 (5.7)	2/231 (0.9)	5.9	0.8	7.52 (2.05–27.6)
Definite stent thrombosis	1/88 (1.1)	2/231 (0.9)	0.4	0.8	0.52 (0.06–4.42)
Clinically driven revascularization	6/88 (6.8)	12/231 (5.2)	6.5	5.2	1.27 (0.66–2.45)
Ischemic stroke	1/88 (1.1)	1/231 (0.4)	0.5	0.9	0.53 (0.07–4.11)
Bleeding (BARC 2, 3, or 5)	8/88 (9.1)	23/231 (10.0)	9.5	9.7	0.97 (0.61–1.68)

The number of patients with events was counted over 1 year. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated in the decreased P2Y₁₂ inhibitor (P2Y₁₂-I) action group and the retained P2Y₁₂-I action group. BARC, Bleeding Academic Research Consortium; CVD, cardiovascular death; HBR, high bleeding risk; IPW, inverse probability weighting; MI, myocardial infarction.

Figure 2.

Inverse probability weighting (IPW)-adjusted Kaplan-Meier curves of the (A) primary ischemic and (B) bleeding outcomes in patients with high bleeding risk (HBR). according to P2Y₁₂ inhibitor action (decreased or retained). CI, confidence interval; HR, hazard ratio; PCI, percutaneous coronary intervention.

Table 3. Interaction Between Treatment Group and HBR Status in Terms of Clinical Outcomes

	Event rates (%)		IPW-adjusted HR (95% CI)	P for interaction
	Decreased P2Y12-I action	Retained P2Y12-I action
Primary ischemic outcome
CVD/MI/ischemic stroke
HBR	9/88 (10)	7/231 (3)	3.70 (1.89–7.25)	0.780
Non-HBR	3/69 (4)	3/230 (1)	3.02 (0.89–10.2)
Primary bleeding outcome
Bleeding (BARC 3 or 5)
HBR	3/88 (3)	16/231 (7)	0.78 (0.40–1.54)	0.219
Non-HBR	2/69 (3)	4/230 (2)	1.78 (0.58–5.48)
Secondary outcomes
Any-cause death
HBR	5/88 (6)	10/231 (4)	2.17 (1.10–4.28)	0.986
Non-HBR	0/69 (0)	1/230 (0.4)	0.00 (0.00–0.00)
CVD
HBR	4/88 (5)	4/231 (2)	3.72 (1.42–9.75)	0.990
Non-HBR	0/69 (0)	1/230 (0.4)	0.00 (0.00–0.00)
MI
HBR	5/88 (6)	2/231 (0.9)	7.81 (2.23–27.4)	0.824
Non-HBR	3/69 (4)	1/230 (0.4)	10.1 (1.30–78.0)
Definite stent thrombosis
HBR	1/88 (1)	2/231 (0.9)	0.75 (0.11–4.91)	0.066
Non-HBR	3/69 (4)	1/230 (0.4)	10.1 (1.30–78.0)
Clinically driven revascularization
HBR	6/88 (7)	12/231 (5)	1.35 (0.72–2.55)	0.135
Non-HBR	6/69 (9)	4/230 (2)	3.27 (1.23–8.66)
Ischemic stroke
HBR	1/88 (1)	1/231 (0.4)	0.71 (0.11–4.44)	0.993
Non-HBR	0/69 (0)	1/230 (0.4)	0.00 (0.00–0.00)
Bleeding (BARC 2, 3, or 5)
HBR	8/88 (9)	23/231 (10)	1.27 (0.77–2.08)	0.230
Non-HBR	3/69 (4)	6/230 (3)	2.35 (0.97–5.71)

The number of patients with events was counted over 1 year. HRs and 95% CIs were calculated in the decreased P2Y₁₂-I action group and the retained P2Y₁₂-I action group. Abbreviations as in Table 2.

When comparing prasugrel and clopidogrel among the retained P2Y₁₂-I action group with HBR status, prasugrel use resulted in a slight reduction in primary ischemic event rates compared with clopidogrel use (prasugrel, 2.8%; clopidogrel, 3.9%), but a marked increase in bleeding events (BARC 3 or 5 bleeding: prasugrel 8.4% vs. clopidogrel 1.9%; BARC 2, 3, or 5 bleeding: prasugrel 12.3% vs. clopidogrel 1.9%; Supplementary Table 3).

Discussion

First, this study demonstrated that CYP2C19 LOF carriers account for 66% of HBR patients undergoing PCI. Second, clopidogrel use in CYP2C19 LOF carriers with HBR was significantly associated with a higher rate of ischemic events after PCI than in those treated with P2Y₁₂-I in whom its action was retained. Third, the association between clopidogrel use after PCI in CYP2C19 LOF carriers and subsequent clinical outcomes was independent of HBR status.

As a DAPT combination for patients with HBR who undergo PCI, European Society of Cardiology guidelines recommend clopidogrel plus aspirin in the setting of chronic coronary syndrome, and clopidogrel plus aspirin or ticagrelor plus aspirin in the setting of ACS (i.e., prasugrel is not recommended in any clinical setting for patients with HBR).¹² The present study indicated that clopidogrel use in CYP2C19 LOF carriers with HBR could contribute to a significantly increased risk of ischemic events. The results of this study are consistent with the results of the Tailored Antiplatelet Initiation to Lessen Outcomes due to Decreased Clopidogrel Response after Percutaneous Coronary Intervention (TAILOR-PCI) trial,²³ in which CYP2C19 LOF carriers who were treated with clopidogrel tended to develop more frequent composite ischemic events (5.9% vs. 4.0%) and less BARC 3 or 5 bleeding (1.5% vs. 2.0%) than those who underwent genotype-guided therapy with clopidogrel, prasugrel, or ticagrelor. Given that the present study showed no interaction between clopidogrel use in CYP2C19 LOF carriers and HBR status in terms of ischemic and bleeding outcomes, the concordance of our results with the TAILOR-PCI trial is convincing. Although the frequency of CYP2C19 LOF variants varies by race (ranging from 35% to 39% in Westerners^23,24 and from 61% to 67% in Asians^3,15,25), the routine use of clopidogrel in patients with HBR may require caution. The current guidelines will be reviewed, and further updates may be needed as more evidence accumulates.

The American College of Cardiology/American Heart Association guidelines for PCI state that genetic testing may be considered for patients at a high risk of poor clinical outcomes but in whom routine use of CYP2C19 genetic testing is not recommended.²⁶ To date, the evidence on the efficacy of CYP2C19 genetic testing after PCI (i.e., genotype-guided therapy) is limited to patients with ACS.^23,24 This may be attributable, in part, to the extent of thrombotic and bleeding risk as a patient characteristic. In the present study, the cumulative rates of primary ischemic events in patients with ACS (n=264) and HBR (n=319) at 1 year were 3.8% and 5.0%, respectively, and the rates of primary bleeding events were 4.6% and 6.0%, respectively. Similarly, in the Platelet Reactivity in Patients with Drug Eluting Stent and Balancing Risk of Bleeding and Ischemic Event (PENDULUM) registry consisting of 6,267 patients, the rates of ischemic events (composite of all-cause death, non-fatal MI, non-fatal stroke, or stent thrombosis) among patients with ACS (n=1,859) and HBR (n=3,185) were 5.2% and 6.8%, respectively, at 1 year,²⁷ with BARC 3 or 5 bleeding event rates of 2.9% and 4.2%, respectively, at 1 year.⁸ These results suggest that the risk of both ischemic and bleeding events in patients with HBR may be comparable to or exceed that of patients with ACS. Moreover, the present study has shown that, compared with clopidogrel use, prasugrel use in the retained P2Y₁₂-I action group with HBR resulted in a slight reduction in primary ischemic event rates, but a marked increase in bleeding events (Supplementary Table 3). Although this result should be interpreted with caution due to the small sample size, clopidogrel may be a better choice for patients with HBR as long as they are confirmed as being CYP2C19 non-LOF carriers. In this context, the efficacy of genotype-guided therapy for patients with HBR may be worthy of future investigation, and well-designed randomized controlled trials will be required. In comparison, it is challenging how to manage patients with HBR who were CYP2C19 LOF carriers. From the comparison between the PENDULUM Mono Registry (short DAPT followed by single antiplatelet therapy with prasugrel) and PENDULUM registry (conventional strategy group), Japanese PCI patients with HBR prescribed prasugrel after short-term DAPT had lower bleeding and ischemic event risks than those prescribed long-term DAPT.²⁸ Therefore, prasugrel monotherapy after short-term DAPT may be a better strategy for both ischemic and bleeding events among those patients.

Our study has several limitations. First, because of its retrospective and observational nature, the conclusions that can be made may be limited. Moreover, potential selection bias in terms of patients’ ischemic and bleeding events may have occurred because only patients who had their CYP2C19 genotypes examined were included. Second, our results may not be widely generalizable outside Japan. Prasugrel was adjusted in the Japanese population to one-third of the dose used in Western populations based on the findings of the Prasugrel Compared with Clopidogrel for Japanese Patients with ACS undergoing PCI (PRASFIT-ACS) study.²⁹ Nonetheless, in a nationwide registry in Japan,³⁰ the risk of bleeding was higher with reduced-dose prasugrel than with standard-dose clopidogrel, which is consistent with the results of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38.¹⁰ Indeed, our study also showed a higher bleeding event rate in patients treated with prasugrel than in those treated with clopidogrel. Third, this study was underpowered to detect differences in some of the clinical outcomes because of the small sample size. Further research is warranted on genotype-guided strategies to improve clinical outcomes after PCI in patients with HBR.

In conclusion, the findings of this study have important implications. Among patients with HBR, clopidogrel use in CYP2C19 LOF carriers was significantly associated with a higher risk of ischemic events after PCI. In addition, the association between clopidogrel use in CYP2C19 LOF carriers after PCI and subsequent ischemic and bleeding outcomes was independent of HBR status.

Acknowledgments

The authors are grateful for the contributions of all the investigators. The authors thank Emily Woodhouse, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Sources of Funding

None.

Disclosures

The authors declare no conflicts of interest associated with this manuscript.

IRB Information

This study was approved by Shiga University of Medical Science Research Ethics Committee (Reference no. R2019-193).

Data Availability

The data underlying this article will be shared upon reasonable request to the corresponding author.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-22-0826

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