Differential Impact of Clinical Factors for Predicting High Platelet Reactivity on Clinical Outcomes in Acute Myocardial Infarction Patients Treated With Clopidogrel and Prasugrel

Abstract

Aims: Several scoring systems, including the ABCD-GENE and HHD-GENE scores incorporating clinical and genetic factors, have been developed to identify patients likely to have high platelet reactivity on P2Y12 inhibitors, leading to increased risks of ischemic events. However, genetic testing is not widely available in daily practice. We aimed to evaluate the differential impact of clinical factors in the scores on ischemic outcomes in patients treated with clopidogrel and prasugrel.

Methods: This bi-center registry included 789 patients with acute myocardial infarction (MI) undergoing percutaneous coronary intervention and treated with either clopidogrel or prasugrel at discharge. The relations of the number of clinical factors included in the ABCD-GENE (age ≥ 75 years, body mass index ＞30 kg/m², chronic kidney disease, and diabetes) and HHD-GENE (hypertension, hemodialysis, and diabetes) scores to the primary endpoint of major cardiovascular events after discharge, a composite of death, recurrent MI, and ischemic stroke, were evaluated.

Results: The number of clinical factors in the ABCD-GENE score was not predictive of ischemic outcomes after discharge in patients treated with clopidogrel and/or prasugrel, while the increase in the number of clinical factors of the HHD-GENE score was associated with an increased risk of the primary endpoint in a stepwise manner in patients on a P2Y12 inhibitor.

Conclusions: Clinical factors listed in the HHD-GENE score may help stratify ischemic risks in patients with acute MI treated with clopidogrel and prasugrel, whereas risk stratification without genetic testing in patients treated with clopidogrel may be challenging.

See editorial vol. 30: 1763-1765

Introduction

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor has been a standard-of-care antithrombotic regimen in patients who present with acute coronary syndrome (ACS) or have undergone percutaneous coronary intervention (PCI) to reduce subsequent thrombotic events^1-3). Clopidogrel, prasugrel, and ticagrelor are the choice of oral P2Y12 inhibitor in the current era, among which clopidogrel remains a broadly used antiplatelet agent in PCI, while the latter two drugs are recommended in the guidelines in patients with ACS^{1, 2)}. The recent European guidelines recommend prasugrel rather than ticagrelor in a setting of non-ST-segment elevation ACS⁴⁾, based on the results of ISAR-REACT 5 trial⁵⁾. Additionally, given that ticagrelor, as compared with clopidogrel, was related to increased trends of both ischemic and bleeding events in East Asian patients with ACS in the randomized PHILO and TICAKOREA trials⁶⁾, prasugrel may be a preferable choice of P2Y12 inhibitor in this patient population. High platelet reactivity (HPR), which indicates inadequate inhibition of platelet function, is known to be a predictor of ischemic events, such as myocardial infarction (MI), stent thrombosis, and stroke in patients undergoing PCI and treated with clopidogrel and prasugrel^{7, 8)}. Although previous studies have shown that the presence of CYP2C19 loss-of-function (LOF) alleles reduces clopidogrel metabolism, it may also impair the metabolism of prasugrel in part^{9, 10)}. In addition to the genetic variant, several clinical factors have been reported to contribute to HPR¹¹⁾. To identify patients at a higher risk of HPR on a P2Y12 inhibitor, some scoring systems such as the ABCD-GENE and HHD-GENE scores have been recently proposed^{12, 13)}, both in which the number of CYP2C19 LOF alleles as well as clinical factors are incorporated to predict a likelihood of having HPR on clopidogrel and prasugrel. Because genetic testing is not widely available in daily clinical practice, whether clinical factors alone in such scoring systems can predict future cardiovascular events may be of clinical interest. In the present study, we aimed to evaluate the differential impact of clinical factors listed in the ABCD-GENE and HHD-GENE scores on ischemic outcomes in acute MI patients treated with clopidogrel and prasugrel.

Patients and Methods

Study Population and Design

This study was a retrospective, bi-center registry study at two tertiary referral hospitals, Chiba University Hospital and affiliated Eastern Chiba Medical Center^14-19). Between January 2012 and March 2020, a total of 1102 patients with acute MI, including ST-segment elevation and non-ST-segment elevation MI, underwent primary PCI procedures at the two centers per local standard practice with a predominant use of radial access, intracoronary imaging, and contemporary drug-eluting stents^20-24). Acute MI was defined based on the fourth universal definition of MI²⁵⁾. Major exclusion criteria included in-hospital death, missing data for calculating risk scores, no follow-up data after discharge, and no clopidogrel or prasugrel prescription and the use of oral anticoagulation at discharge (Fig.1). Finally, 789 patients with acute MI undergoing PCI and treated with either clopidogrel or prasugrel were included into the present analysis. No genetic and platelet function testing was performed in this study. Written informed consent for the PCI procedures was obtained from all participants, and informed consent for the present study was ascertained via opt-out. This study was conducted in accordance with the Declaration of Helsinki and was approved by the ethical committee at each hospital.

Fig.1. Study flow

MI, myocardial infarction; OAC, oral anticoagulation; PCI, percutaneous coronary intervention.

Risk Scoring Systems

In the present study, the ABCD-GENE and HHD-GENE scores were tested^{12, 13)}. The ABCD-GENE score was developed to identify patients with HPR on clopidogrel from the dataset of PCI populations in the United States and Canada, consisting of four clinical factors such as age ≥ 75 years, body mass index ＞30 kg/m², chronic kidney disease (CKD) evaluated with glomerular filtration rate ＜60 ml/min, and diabetes, in addition to the genetic factor (i.e., the number of CYP2C19 LOF alleles)¹²⁾. Significant association of the higher original ABCD-GENE score (e.g., ≥ 10) with ischemic outcomes on clopidogrel treatment has been confirmed in previous studies^26-29). Although the original ABCD-GENE score assigns four points to age and body mass index and three points to CKD and diabetes, all four clinical factors were equally counted as one variable, and the genetic factor was disregarded in the present study, ranging from zero to four. CKD was defined as an estimated glomerular filtration rate (eGFR) ＜60 ml/min/1.73 m², and diabetes was defined as a previous diagnosis of diabetes or previous glucose-lowering medications, or hemoglobin A1c ≥ 6.5% on admission³⁰⁾.

The HHD-GENE score was created to identify patients with HPR on prasugrel in our previous report and was derived from PCI populations in Japan¹³⁾, which incorporates three clinical factors (hypertension, hemodialysis, and diabetes) and a genetic testing result. As with the ABCD-GENE score, the three clinical factors were counted as one variable and the number of CYP2C19 LOF alleles was not included in the calculation of the HHD-GENE score in this study, ranging from zero to three. The relation between the HHD-GENE score and clinical outcomes has not been reported yet. Hypertension was defined as having a previous diagnosis of hypertension or previous antihypertensive medications or a new diagnosis of hypertension during the index hospitalization with systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg³⁰⁾. A bleeding risk was evaluated using the international criteria by the Academic Research Consortium for high bleeding risk³¹⁾.

Endpoint and Statistical Analysis

Patients were divided into two groups; those treated with clopidogrel and prasugrel at discharge (Fig.1). Clopidogrel has been widely used in clinical practice since 2006, while prasugrel became available in 2014 in Japan. Follow-up data were collected from medical records at Chiba University Hospital and Eastern Chiba Medical Center. The primary endpoint of the present study was major cardiovascular events (MACE) after discharge, a composite of all-cause death, recurrent MI, and ischemic stroke, adjudicated with the Academic Research Consortium-2 consensus document³²⁾. The main interest of this study was to evaluate whether the clinical factors incorporated in the ABCD-GENE and HHD-GENE scores are associated with MACE after discharge in acute MI patients undergoing PCI and treated with clopidogrel and/or prasugrel. Major bleeding was defined as Bleeding Academic Research Consortium type 3 or 5 ³³⁾. Potential factors associated with MACE after discharge, including clopidogrel and prasugrel treatment, were also evaluated as an exploratory analysis, but this was not the primary interest of the present study.

All statistical analyses were performed using JMP Pro 15.0.0 (SAS Institute, Cary, USA) and SAS software version 9.3 (SAS Institute, Cary, USA). Data are expressed as mean±standard deviation, median [interquartile range], or frequency with percentage. Continuous variables were assessed with Student t-test or Mann–Whitney U test, and categorical variables were compared with Fisher’s exact test. The Kaplan–Meier analysis with the log-rank test was performed to estimate MACE-free survival after discharge in patients treated with clopidogrel and prasugrel. A Cox proportional-hazard model was used to estimate unadjusted and adjusted hazard ratios with corresponding 95% confidence intervals of MACE after discharge. Age, choice of P2Y12 inhibitor, and factors associated with MACE in univariable analysis (p＜0.05) were included in the multivariable model. Because eGFR and hemodialysis were collinear to each other, hemodialysis was not included in the multivariable analysis with eGFR. A p-value of 0.05 was considered statistically significant.

Results

Of the 789 acute MI patients undergoing PCI, 328 (41.6%) and 461 (58.4%) received clopidogrel and prasugrel at discharge, predominantly as a part of DAPT with aspirin. Supplementary Fig.1 displays a temporal trend of clopidogrel and prasugrel use from 2012 to 2020. Table 1 lists baseline characteristics. Age ≥ 75 years, body mass index ＞30 kg/m², hypertension, diabetes, CKD, and hemodialysis were found in 196 (24.8%), 56 (7.1%), 545 (69.1%), 293 (37.1%), 296 (37.5%), and 23 (2.9%), respectively. During the median follow-up period of 457 [312, 916] days (551 [305, 1412] days in the clopidogrel group vs. 420 [316, 751] days in the prasugrel group, p＜0.001), 55 (7.0%) patients experienced MACE (Table 2). In patients treated with clopidogrel, the incidence of MACE was higher than in those treated with prasugrel (Table 2). The Kaplan-Meier analysis demonstrated that among patients treated with clopidogrel, the number of clinical factors in the ABCD-GENE score was significantly associated with risks of MACE in a non-stepwise manner, while the increase in the number of clinical factors in the HHD-GENE score resulted in an increased risk of MACE (Fig.2). Among patients treated with prasugrel, the clinical factors of the ABCD-GENE score were not associated with MACE after discharge, while the number of those of the HHD-GENE score was significantly associated in a stepwise manner (Fig.3). In the entire study population on either clopidogrel or prasugrel, the results were similar to those in patients treated with clopidogrel (Supplementary Fig.2). Patients having the number of clinical factors of the ABCD-GENE score ≥ 3 (i.e., those corresponding to the original ABCD-GENE score ≥ 10) did not result in a significantly higher risk of MACE than their counterpart in the cohort of clopidogrel (Supplementary Fig.3). The multivariable analysis identified hypertension, peripheral artery disease, and lower eGFR as factors significantly associated with MACE after discharge (Supplementary Table 1).

Supplementary Fig.1.

Temporal trend of clopidogrel and prasugrel use from 2012 to 2020

Table 1. Baseline characteristics

Variable	All (n = 789)	Clopidogrel (n = 328)	Prasugrel (n = 461)	p value
Age (years)	66.7±11.8	67.5±12.0	66.1±11.6	0.09
Men	609 (77.2%)	247 (75.3%)	362 (78.5%)	0.30
Body mass index (kg/m2)	24.4±3.7	24.2±3.8	24.5±3.7	0.21
Hypertension	545 (69.1%)	249 (75.9%)	296 (64.2%)	＜0.001
Diabetes	293 (37.1%)	122 (37.2%)	171 (37.1%)	1.00
Dyslipidemia	534 (67.7%)	235 (71.6%)	299 (64.9%)	0.045
Current smoker	276 (35.0%)	111 (33.8%)	165 (35.8%)	0.60
Prior myocardial infarction	47 (6.0%)	28 (8.5%)	19 (4.1%)	0.01
Atrial fibrillation	10 (1.3%)	6 (1.8%)	4 (0.9%)	0.33
Peripheral artery disease	14 (1.8%)	9 (2.7%)	5 (1.1%)	0.10
Hemodialysis	23 (2.9%)	8 (2.4%)	15 (3.3%)	0.67
eGFR (ml/min/1.73 m2)	66.6±23.5	65.9±23.8	67.1±23.3	0.47
Hemoglobin (g/dl)	13.9±2.1	13.5±2.3	14.2±2.0	＜0.001
LVEF (%)	49.9±11.2	49.6±11.2	50.2±11.3	0.42
ARC-HBR	291 (36.9%)	137 (41.8%)	154 (33.4%)	0.02
Clinical presentation				0.25
STEMI	521 (66.0%)	209 (63.7%)	312 (67.7%)
NSTEMI	268 (34.0%)	119 (36.3%)	149 (32.3%)
Medication at discharge
Aspirin	783 (99.2%)	322 (98.2%)	461 (100%)	0.005
ACE-I/ARB	678 (85.9%)	281 (85.7%)	397 (86.1%)	0.92
β-blocker	582 (73.8%)	239 (72.9%)	343 (74.4%)	0.68
Statin	738 (93.5%)	301 (91.8%)	437 (94.8%)	0.11
NSAIDs/steroids	51 (6.5%)	22 (6.7%)	29 (6.3%)	0.88
PPI	758 (96.1%)	305 (93.0%)	453 (98.3%)	＜0.001

ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ARC-HBR, Academic Research Consortium for high bleeding risk; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; NSAIDs, non-steroidal anti-inflammatory drugs; NSTEMI, non-ST-segment elevation myocardial infarction; PPI, proton pump inhibitor; STEMI, ST-segment elevation myocardial infarction.

Table 2. Clinical events after discharge

Variable	All (n = 789)	Clopidogrel (n = 328)	Prasugrel (n = 461)	p value
MACE	55 (7.0%)	35 (10.7%)	20 (4.3%)	＜0.001
All-cause death	51 (6.5%)	33 (10.1%)	18 (3.9%)	＜0.001
Recurrent MI	28 (3.5%)	18 (5.5%)	10 (2.2%)	0.02
Ischemic stroke	15 (1.9%)	10 (3.0%)	5 (1.1%)	0.06
Major bleeding events	24 (3.0%)	16 (4.9%)	8 (1.7%)	0.02

MACE, major adverse cardiovascular events; MI, myocardial infarction.

Fig.2. Relations of the number of clinical factors in the ABCD-GENE and HHD-GENE scores to MACE after discharge in patients treated with clopidogrel

MACE, major cardiovascular events.

Fig.3. Relations of the number of clinical factors in the ABCD-GENE and HHD-GENE scores to MACE after discharge in patients treated with prasugrel

MACE, major cardiovascular events.

Supplementary Fig.2. Relations of the number of clinical factors in the ABCD-GENE and HHD-GENE scores to MACE after discharge in patients treated with clopidogrel and prasugrel

MACE, major cardiovascular events.

Supplementary Fig.3. Relations of the number of clinical factors ≥ 3 in the ABCD-GENE score to MACE after discharge in patients treated with clopidogrel

MACE, major cardiovascular events.

Supplementary Table 1. Multivariable analysis for MACE after discharge

Variable	Univariable		Multivariable
	HR (95% CI)	p value	HR (95% CI)	p value
Age (years)	1.02 (1.00-1.05)	0.08	1.00 (0.98-1.03)	0.81
Men	0.85 (0.46-1.56)	0.59
Body mass index (kg/m2)	1.00 (0.93-1.08)	0.93
Hypertension	3.59 (1.54-8.39)	0.003	2.78 (1.18-6.60)	0.02
Diabetes	1.49 (0.88-2.54)	0.13
Dyslipidemia	1.22 (0.68-2.22)	0.51
Current smoker	0.54 (0.29-1.00)	0.050
Prior myocardial infarction	1.34 (0.53-3.38)	0.53
Atrial fibrillation	1.89 (0.26-13.72)	0.53
Peripheral artery disease	7.89 (3.11-19.96)	＜0.001	3.79 (1.42-10.10)	0.008
Hemodialysis	6.18 (2.78-13.78)	＜0.001
eGFR (ml/min/1.73 m2)	0.98 (0.97-0.99)	＜0.001	0.98 (0.97-1.00)	0.01
Hemoglobin (g/dl)	0.89 (0.79-0.99)	0.04	0.99 (0.86-1.14)	0.92
LVEF (%)	0.98 (0.96-1.01)	0.18
STEMI presentation	1.28 (0.71-2.29)	0.41
Aspirin	0.12 (0.02-0.91)	0.04	0.16 (0.02-1.21)	0.08
Clopidogrel vs. prasugrel	1.61 (0.90-2.87)	0.11	1.38 (0.76-2.50)	0.29
ACE-I/ARB	0.62 (0.31-1.24)	0.18
β-blocker	1.02 (0.56-1.87)	0.94
Statin	0.44 (0.21-0.94)	0.03	0.64 (0.29-1.41)	0.27
NSAIDs/steroids	1.46 (0.23-9.32)	0.69
PPI	3.04 (0.42-22.13)	0.27

ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CI, confidence intervals; eGFR, estimated glomerular filtration ratel HR, hazard ratio; LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular events; MI, myocardial infarction; NSAIDs, non-steroidal anti-inflammatory drugs; PPI, proton pump inhibitor; STEMI, ST-segment elevation myocardial infarction.

Discussion

The present study demonstrated that among the patients with acute MI undergoing PCI, the prevalence of clinical components of the ABCD-GENE and HHD-GENE scores varied widely. Without genetic testing, the number of the ABCD-GENE score was not directly predictive of ischemic events after discharge in patients treated with clopidogrel and/or prasugrel, while the increase in the number of clinical factors of the HHD-GENE score was associated with an increased risk of MACE in patients on a P2Y12 inhibitor. These results suggest the importance of dedicated risk scoring systems for predicting outcomes in specific populations and the uncertainness of estimating HPR on clopidogrel without genetic testing.

Impact of High Platelet Reactivity on Ischemic Events

The advent of P2Y12 inhibitor as a part of DAPT contributed to improved clinical outcomes in patients with ACS and/or undergoing PCI^{1, 2)}. However, HPR on P2Y12 inhibitors, namely an inadequate platelet function inhibition, has emerged as a clinical concern. In the pivotal ADAPT-DES study (n=8582), HPR on clopidogrel was significantly associated with increased risks of stent thrombosis (1.3% vs. 0.5%, p=0.0002), MI (3.9% vs. 2.7%, p=0.002), and all-cause mortality (2.4% vs. 1.5%, p=0.002) at one year in patients undergoing PCI with drug-eluting stent implantation⁷⁾. Even with prasugrel, a potent P2Y12 inhibitor, the PENDULUM registry (n=6267) demonstrated that patients having HPR on a P2Y12 inhibitor (approximately two-thirds were on prasugrel) were at a higher risk of major adverse cardiac and cerebrovascular events after PCI in a contemporary setting⁸⁾. Thus, the identification of HPR and therapeutic intervention has become a clinical interest in patients undergoing PCI. Whether the guided selection of an antiplatelet regimen with genetic and platelet function testing is effective in improving outcomes has been tested in numerous randomized control trials, most of which were not powered for hard clinical endpoints and thus failed to show the superiority of genetic and platelet function test guidance in individual studies. However, a recent meta-analysis including 20,743 patients undergoing PCI from 11 randomized and three observational studies showed that guided selection of antiplatelet therapy improved both efficacy and safety outcomes³⁴⁾. Of note, in a subgroup of patients undergoing an escalation strategy in choosing an antithrombotic regimen, guided therapy was associated with a reduced risk of ischemic events while in a subgroup of patients undergoing a de-escalation strategy, guided therapy resulted in a reduction in bleeding events³⁴⁾. Another recent meta-analysis confirmed the potential usefulness of guided P2Y12 inhibitor therapy as compared with a routine selection of antiplatelet agents in patients with ACS³⁵⁾. Therefore, the identification of HPR on P2Y12 inhibitors may be clinically relevant, although genetic and platelet function testing in daily practice is challenging.

Clinical Factors of the ABCD-GENE and HHD-GENE Scores

The traditional understanding often includes that HPR on clopidogrel is driven solely by the CYP2C19 LOF alleles, while prasugrel is a P2Y12 inhibitor free from the influence of the genetic variant. However, several clinical factors are known to contribute to HPR on clopidogrel and prasugrel^11-13), and even prasugrel is, in part, subject to the impaired metabolism by CYP2C19 LOF alleles^{9, 10)}. In this context, the ABCD-GENE and HHD-GENE scores have been developed to identify patients with a higher likelihood of having HPR on clopidogrel and prasugrel, incorporating both clinical and genetic factors^{12, 13)}. In the present study, however, we aimed to assess the prognostic impact of clinical factors listed in the ABCD-GENE and HHD-GENE scores without information on the genetic variant for the potential clinical usefulness. Although several recent studies have shown the diagnostic ability of the original ABCD-GENE score on the presence of clopidogrel HPR and clinical outcomes^{12, 26-29)}, whether the clinical factors alone can stratify ischemic risks in patients undergoing PCI remains unknown. In the present study, although the number of clinical factors of the ABCD-GENE score was associated with MACE after discharge in patients treated with clopidogrel, the risk was not stratified in a stepwise fashion, suggesting that the clinical factors alone were not sufficiently predictive for HPR and subsequent ischemic outcomes. Given that assigned points to the number of CYP2C19 LOF alleles are considerably higher in the ABCD-GENE score for predicting HPR on clopidogrel (i.e., 6 and 24 for the cutoff value of 10) than in the HHD-GENE score for HPR on prasugrel (i.e., 1 and 2 for the cutoff value of 5) and that the effect of clopidogrel as compared with potent P2Y12 inhibitors such as prasugrel and ticagrelor is based primarily on the presence of CYP2C19 LOF carrier status^{12, 13, 36)}, it is conceivable that the identification of HPR on clopidogrel without genetic testing is difficult. Even in patients having the number of clinical factors of the ABCD-GENE score ≥ 3, indicating that those should have the original ABCD-GENE score ≥ 10, MACE rates were not significantly higher than in their counterparts (Supplementary Fig.3). The greater impact of genetic factors in the ABCD-GENE score than in the HHD-GENE score may be particularly important in East Asian patients because they are more likely to have CYP2C19 LOF alleles than those in Western countries^{37, 38)}.

CYP3A4 is a great contributor to the metabolism of prasugrel, although CYP2C19 also plays a partial part in vivo⁹⁾. However, as abovementioned, the impact of CYP2C19 LOF carrier status on the likelihood of having HPR is less in patients treated with prasugrel than in those treated with clopidogrel. Thus, it is hypothesized that patients having more clinical factors reportedly associated with HPR on prasugrel are likely to develop ischemic events. Indeed, the increase in the number of clinical factors in the HHD-GENE score was associated with an increased risk of MACE in a stepwise manner among patients treated with prasugrel. Whether the risk stratification with the clinical factors in the HHD-GENE score was attributable to HPR on prasugrel remains unknown, but the present study demonstrated the potential usefulness of the HHD-GENE score in clinical practice. Interestingly, the number of clinical factors in the HHD-GENE score was also predictive for MACE after discharge in patients treated with clopidogrel. Because diabetes is included in the two scores, hypertension and hemodialysis over CKD were considered to result in risk stratification. The sub-analysis of ADAPT-DES trial indicated the presence of hypertension as a significant factor associated with HPR on clopidogrel, in which hypertensive patients had a higher risk of ischemic events, a composite of cardiac death, MI, or stent thrombosis, as shown in the present study³⁹⁾. Additionally, although the ABCD-GENE score included CKD as a clinical factor, patients with end-stage CKD, including hemodialysis, are known to have extremely higher risks of cardiovascular disease⁴⁰⁾, potentially resulting in differential impact of clinical factors between the ABCD-GENE and HHD-GENE scores on ischemic outcomes after discharge in this study. The clinical implications of hypertension and hemodialysis on the presence of HPR and ischemic outcomes in patients treated with clopidogrel deserve further investigations. Nevertheless, when genetic and platelet function tests cannot be performed in daily practice, the three clinical factors in the HHD-GENE score such as hypertension, hemodialysis, and diabetes might simply aid in stratifying ischemic risks in patients with acute MI undergoing PCI and treated with clopidogrel and prasugrel.

Study Limitations

The present study has some limitations. This study was a retrospective study with a moderate sample size. Although all patients were on either clopidogrel or prasugrel without oral anticoagulation at discharge, follow-up information on medication is lacking. However, given that patients included in this study were presented with acute MI and underwent primary PCI, it is conceivable that most of those were on DAPT with aspirin plus a P2Y12 inhibitor for at least 6–12 months after the index event according to the guideline recommendation during the study period^{1, 41)}. Because of the temporal availability and trends in using clopidogrel and prasugrel in Japan (Supplementary Fig.1), the follow-up period was significantly longer in the clopidogrel group than in the prasugrel group, potentially resulting in an increased risk of MACE in patients treated with clopidogrel. Indeed, the multivariable analysis did not identify the choice of P2Y12 inhibitor (i.e., clopidogrel vs. prasugrel) as a factor significantly associated with MACE after discharge. The main interest of this study was to evaluate the impact of clinical factors in the ABCD-GENE and HHD-GENE scores without genetic testing as is in daily practice, but this approach may have impaired the usefulness of the ABCD-GENE score, in which the contribution of CYP2C19 LOF alleles is much more than that of clinical factors¹²⁾. Due to the lack of platelet function testing, whether the clinical outcomes shown in the present study were accountable for HPR on the P2Y12 inhibitors was unclear. In addition, because of the lack of genetic testing in this study, the direct comparison of the original ABCD-GENE and HHD-GENE scores with clinical factors alone in such scoring systems on diagnostic ability was not feasible. Nevertheless, we believe the present results may be of clinical interest because genetic and platelet function testing is not widely available in daily clinical practice.

Conclusions

Among patients with acute MI undergoing PCI, the increase in the number of clinical factors incorporated in the HHD-GENE score, a risk scoring system for HPR on prasugrel, including hypertension, hemodialysis, and diabetes was progressively associated with an increased risk of MACE after discharge in patients treated with clopidogrel and prasugrel, while the number of clinical factors in the ABCD-GENE score, a model for HPR on clopidogrel, did not predict future ischemic outcomes in patients on prasugrel and was associated with MACE in those on clopidogrel only in a non-stepwise manner. These findings suggest that genetic testing may be needed in predicting HPR on clopidogrel and that the HHD-GENE score might help identify patients at high ischemic risk when treated with clopidogrel and prasugrel.

Disclosure

Yuichi Saito reports honoraria from Daiichi Sankyo. Yoshio Kobayashi reports honoraria and research grants from Daiichi Sankyo. Other authors declare nothing to disclose.

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