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Effects of CYP2C19 allelic variants on inhibition of platelet aggregation and major adverse cardiovascular events in Japanese patients with acute coronary syndrome: The PRASFIT-ACS study
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, JapanNational Cerebral and Cardiovascular Center, Osaka, Japan
We examined the effects of cytochrome P450 2C19 (CYP2C19) polymorphisms on the efficacy and safety of prasugrel and clopidogrel in a post hoc analysis of the PRASugrel compared with clopidogrel For Japanese patIenTs with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) (PRASFIT-ACS) study.
Methods
Japanese ACS patients undergoing PCI were randomized (double-blind) to receive prasugrel (loading/maintenance dose: 20/3.75 mg) or clopidogrel (300/75 mg) plus aspirin for 24–48 weeks. Pharmacogenomic analyses were conducted in 773/1363 patients. P2Y12 reaction units (PRU) were determined using the VerifyNow® P2Y12 assay (Accumetrics, San Diego, CA, USA). CYP2C19 genotypes were classified as extensive metabolizers (EM), intermediate metabolizers (IM), and poor metabolizers (PM).
Results
Overall, 39.2% and 60.8% of patients in the prasugrel group and 35.2% and 64.8% of patients in the clopidogrel group were classified as EM and IM + PM, respectively. Among EM patients, PRU was significantly lower in the prasugrel group than in the clopidogrel group at 2–4 and 5–12 h after the loading dose, but was similar in both groups from week 4 onwards. Among IM + PM patients, PRU was significantly lower in the prasugrel group than in the clopidogrel group throughout the study. Among EM patients, the incidence of major adverse cardiovascular events (MACE) at 24 weeks was 11.8% in the prasugrel group and 11.9% in the clopidogrel group [hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.50–1.96]. Among IM + PM patients, the incidence of MACE was 9.3% in the prasugrel group and 12.5% in the clopidogrel group (HR: 0.78, 95% CI: 0.45–1.35). The incidences of major, minor, and clinically relevant bleeding were similar between the two groups for each genotype.
Conclusions
Prasugrel showed more consistent antiplatelet effects than clopidogrel in Japanese ACS patients irrespective of the CYP2C19 phenotype.
The 2009 Japanese Guidelines for the Management of Anticoagulant and Antiplatelet Therapy in Cardiovascular Disease recommend the use of antiplatelet agents for preventing reinfarction following percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) [
]. Clopidogrel, an irreversible inhibitor of the platelet P2Y12 adenosine diphosphate receptor, has become the standard therapeutic drug in this setting and is often administered in combination with or instead of aspirin to prevent thrombosis. Because clopidogrel is a prodrug that is biotransformed into its active moiety by cytochrome P450 enzymes, particularly CYP2C19, genetic variants of CYP2C19 were reported to interfere with the metabolic activation and extent of platelet inhibition during treatment with clopidogrel [
CYP2C19*2 and *17 alleles have a significant impact on platelet response and bleeding risk in patients treated with prasugrel after acute coronary syndrome.
Effects of coexisting polymorphisms of CYP2C19 and P2Y12 on clopidogrel responsiveness and clinical outcome in patients with acute coronary syndromes undergoing stent-based coronary intervention.
]. Moreover, the presence of at least one reduced-function CYP2C19 allele was associated with increased risk of major adverse cardiovascular events (MACE), particularly stent thrombosis, in clopidogrel-treated patients [
Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.
Impact of CYP2C19 genetic testing on provider prescribing patterns for antiplatelet therapy after acute coronary syndromes and percutaneous coronary intervention.
] has been proposed before starting clopidogrel therapy to identify patients likely to show reduced antiplatelet activity.
Prasugrel is a newer thienopyridine antiplatelet agent that also irreversibly inhibits platelet P2Y12 receptors. Like clopidogrel, prasugrel is a prodrug that is biotransformed in vivo by members of the cytochrome P450 system, although CYP3A4 and CYP2B6 seem to be the predominant activators of prasugrel [
]. In vivo studies have demonstrated that the antiplatelet activity (i.e. inhibition of platelet aggregation) of prasugrel is greater than that of both clopidogrel and ticlopidine when either drug was administered alone or in combination with aspirin [
The large-scale Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) subsequently confirmed that prasugrel [loading dose/maintenance dose (LD/MD): 60/10 mg] significantly reduced the incidence of ischemic events, especially stent thrombosis, but had a higher incidence of bleeding than clopidogrel (LD/MD: 300/75 mg) in ACS patients [
]. More recently, the PRASugrel compared with clopidogrel For Japanese patIenTs with ACS undergoing PCI (PRASFIT-ACS) study revealed that a prasugrel dosing regimen (LD/MD: 20/3.75 mg) that was adjusted for Japanese patients was associated with a low incidence of MACE and with a low risk of clinically serious bleeding [
]. These results suggest that prasugrel may represent an effective and safe alternative to clopidogrel in Japanese ACS patients undergoing PCI.
In Japan, the prevalence of patients with genetic variants of CYP2C19 that are responsible for poor metabolism of clopidogrel is much higher (18–23%) than that in Western countries (e.g. 2–3% in the USA and ∼3.5% in Europe) [
], about three-quarters had CYP2C19 variant alleles and the majority of patients classified as intermediate metabolizers (IM) or poor metabolizers (PM) displayed increased platelet reactivity. However, the incidence of adverse outcomes was not apparently affected by the CYP2C19 status [
]. In another study of Japanese patients, platelet reactivity was significantly greater in patients with CYP2C19 variant alleles among patients with ACS or stable angina [
]. It was also noted that cardiovascular events in patients with CYP2C19 variant alleles were more frequent in those patients with ACS than in those with stable angina [
]. Although genetic variants of CYP2C19 are not thought to influence prasugrel metabolism because of the minor contribution of this isoform to the activation of prasugrel, it is important to verify that CYP2C19 genetic variants do not reduce platelet inhibition or increase the risk of MACE in Japanese ACS patients. To examine this issue, 773/1363 patients in the PRASFIT-ACS study underwent genetic testing to determine the influence of CYP2C19 polymorphisms on the efficacy and safety of prasugrel and clopidogrel.
Materials and methods
Study design
PRASFIT-ACS was a randomized, double-blind, double-dummy, parallel-group study conducted at 162 centers in Japan between December 2010 and June 2012 [
]. The study consisted of a 24–48-week treatment period followed by a 14-day follow-up period. Patients were randomly allocated to prasugrel (LD/MD: 20/3.75 mg) or clopidogrel (300/75 mg). The LD was to be administered before PCI, except in urgent cases, when it could be administered up to 1 h after leaving the cardiac catheterization laboratory. The MD was administered once daily after breakfast, starting on the day after the LD, and was continued for the remainder of the treatment period. All patients received aspirin (81–330 mg for the first dose and 81–100 mg/day thereafter) throughout the treatment period. The concomitant use of other antiplatelet drugs, anticoagulant drugs, thrombolytic drugs, or chronic administration of oral, non-steroidal anti-inflammatory drugs was prohibited.
Clinical visits were scheduled every 2–4 weeks for the first 12 weeks, and every 12 weeks thereafter. Although 48 weeks was the recommended duration of study drug administration, the investigators could complete drug administration at week 24 taking into account stent type and the recommended duration of antiplatelet therapy as stated in the package inserts.
The study was conducted according to the Declaration of Helsinki and Good Clinical Practice and was approved by institutional review boards at all participating institutions. The study was registered on the Japan Pharmaceutical Information Center database (identifier: JapicCTI-101339).
], this study involved Japanese ACS patients who were scheduled for coronary artery stenting and who satisfied the following major eligibility criteria: males/females; age ≥20 years; presence of chest discomfort or ischemic symptoms lasting ≥10 min within 72 h before randomization; and ST-segment deviation of ≥1 mm, or T-wave inversion of ≥3 mm, or elevated levels of cardiac biomarkers for necrosis. The main exclusion criteria included the following: pancytopenia or aplastic anemia; history of intracranial bleeding; history of ischemic stroke/transient ischemic attack; history of or predisposition to hemorrhagic disease; poorly controlled hypertension; severe hepatic or renal impairment; New York Heart Association grade IV heart failure; and administration of thienopyridine or thrombolytic drugs within 5 days before starting the study drug or a thrombolytic drug within 24 h before starting the study drug. All of the patients provided informed consent before enrolment.
Genotyping
Genotyping was performed at LSI Medience Corporation (Tokyo, Japan). Genomic DNA was isolated using a QIAamp Blood Kit (Qiagen, Hilden, Germany) and the CYP2C19 single nucleotide polymorphisms (SNPs) resulting in point mutations of 681G>A and 636G>A were detected using the Invader DNA assay method (Third Wave Technologies, Madison, WI, USA). The SNP genotypes were translated into star-allele genotypes and the patients were classified as extensive metabolizers (EM; *1/*1), IM (*1/*2, *1/*3), and PM (*2/*2, *2/*3, *3/*3), as previously described [
]. Genetic tests were performed in 773 patients who agreed to take the study drugs and who provided consent for these tests.
Pharmacodynamic analyses
Pharmacodynamic tests of platelet inhibition were conducted using the VerifyNow® P2Y12 assay (Accumetrics, San Diego, CA, USA) at each institution. The VerifyNow® assay measures adenosine diphosphate-induced platelet function as an increase in light transmittance and reports values in P2Y12 reaction units (PRU) [
]. For the purpose of this report, efficacy outcomes included MACE occurring through week 24, cardiovascular death, nonfatal myocardial infarction (MI), nonfatal ischemic stroke, all-cause death, nonfatal stroke, revascularization, and stent thrombosis.
Safety
Bleeding events were recorded from the start of administration to 14 days after treatment completion/discontinuation, and were classified as follows: major Thrombolysis in Myocardial Infarction (TIMI) bleeding (life-threatening or fatal), minor TIMI bleeding, clinically relevant bleeding, and other bleeding [
Statistical analyses were conducted in the following patient sets: pharmacogenomic analysis set (all patients who provided informed consent, underwent genetic testing, received at least one dose of the allocated study drug, and did not have a serious protocol violation), pharmacodynamic analysis set (all patients who underwent pharmacodynamic tests of platelet inhibition), full analysis set (all patients who took at least one dose of the allocated study drug, who did not have a serious protocol violation, and who had data collected after starting administration of the study drug), and the safety analysis set (all patients who took at least one dose of the allocated study drug and who did not have a serious protocol violation) [
For this report, efficacy and safety analyses were done after stratifying patients according to the cytochrome P450 2C19 phenotype (EM, IM, and PM). Because of the small number of PM patients, they were combined with the IM patients for statistical analyses. PRU is summarized as the mean and standard deviation at each time point, and was compared among the EM, IM, and PM patients using repeated-measures analysis of variance. To handle missing data, we used the mixed-effect model repeated measure rather than excluding subjects with missing data or imputing missing data using the last observation carried forward method. The mixed-effect model repeated measure was reported to be associated with lower empirical bias and Type 1 error rates compared with the last observation carried forward approach [
Hazard ratios (HRs) with two-sided 95% confidence intervals (CIs) for the prasugrel group relative to the clopidogrel group were calculated for the efficacy endpoints using the Cox proportional hazard model with adjustment for age (<75 vs. ≥75 years) and the number of lesions treated during PCI (no first PCI, one lesion, or multiple lesions). HRs and 95% CIs for bleeding events were determined using the Cox proportional hazard model with adjustment for body weight (<50 vs. ≥50 kg) and puncture site in the first PCI (femoral, yes vs. no).
All analyses were performed used SAS version 9.2 (SAS Institute, Cary, NC, USA).
], 1465 patients gave informed consent, 1385 were randomized and 1363 received either prasugrel (n = 685) or clopidogrel (n = 678) and were included in the full analysis set. Of these, 773 patients underwent genetic testing (prasugrel: n = 390; clopidogrel: n = 383) and were included in the pharmacogenomic analysis set. The characteristics of patients in the pharmacogenomics analysis set are summarized according to treatment group in Supplementary Table 1 and according to CYP2C19 phenotype and treatment group in Supplementary Table 2. Approximately 80% of patients were male, the mean age was about 64 years, almost 20% were ≥75 years old, and approximately 50% had unstable angina/non-ST-segment elevation MI. The overall characteristics of this analysis set are similar to those of the full analysis set reported elsewhere [
]. The proportions of patients defined as EM, IM, and PM were 39.2%, 41.0%, and 19.7%, respectively, in the prasugrel group, and 35.2%, 44.6%, and 20.1%, respectively, in the clopidogrel group (Supplementary Table 1). These proportions are fairly similar to those reported in prior studies of Asian patients (EM/ultrarapid metabolizers: 43.6%, IM: 44.4%, PM: 8.4% [
]). The number of PM patients was small, and there were slight but significant differences in some baseline characteristics between the prasugrel and clopidogrel groups of patients, especially in the IM and PM patients; these differences between the two treatment groups were attenuated when we combined the IM and PM patients into a single group (i.e. IM + PM patients) (Supplementary Table 2). In TRITON-TIMI 38 [
], the IM and PM patients were classified as carriers of reduced function alleles. Therefore, we analyzed efficacy and safety in two subgroups of patients, EM and IM + PM, in each treatment group.
Inhibition of platelet aggregation
The extent of platelet inhibition, determined by PRU, was similar in the clopidogrel and prasugrel groups among EM patients from week 4 onward, although prasugrel showed a quicker onset of action, with significantly lower PRU at 2–4 h and 5–12 h after the LD (Fig. 1A ). By contrast, among IM + PM patients, PRU was significantly lower in the prasugrel group than in the clopidogrel group throughout the study period, including 2–4 h and 5–12 h after the LD (Fig. 1B).
Fig. 1Comparison of platelet aggregation determined by the VerifyNow® assay between the prasugrel and clopidogrel groups in extensive metabolizers (A) and intermediate and poor metabolizers (B). ***p < 0.0001 and **p < 0.001 vs. clopidogrel (tested using repeated-measures analysis of variance as a statistical model). Values are presented as the mean ± standard deviation (pharmacodynamic and pharmacogenomic analysis sets). h, hours; LD, loading dose; PRU, P2Y12 reaction units; w, weeks.
As shown in Fig. 2 and Table 1, the incidence of MACE at 24 weeks was 10.3% in the prasugrel group and 12.3% in the clopidogrel group in all patients included in the pharmacogenomic analysis set (n = 773). The HR was 0.84 (95% CI: 0.55–1.28), similar to that in the full analysis set (n = 1363; HR: 0.77; 95% CI: 0.56–1.07). In EM patients, the incidence of MACE was 11.8% in the prasugrel group and 11.9% in the clopidogrel group (HR: 0.99; 95% CI: 0.50–1.96). In IM + PM patients, the incidence of MACE was 9.3% in the prasugrel group and 12.5% in the clopidogrel group (HR: 0.78; 95% CI: 0.45–1.35) (Table 1). The HR for MACE at 48 weeks was similar to the HR for MACE at 24 weeks. In EM patients, the incidence of MACE at 48 weeks was 13.1% in the prasugrel group and 14.1% in the clopidogrel group (HR: 0.93; 95% CI: 0.49–1.76). In IM + PM patients, the incidence of MACE at 48 weeks was 10.5% in the prasugrel group and 12.5% in the clopidogrel group (HR: 0.89; 95% CI: 0.53–1.51). Regarding other efficacy components, the incidences of nonfatal MI and revascularization were similar between the two treatment groups, while the incidences of the other components were low in all patients, including the EM and IM + PM subgroups (Table 1).
Fig. 2Forest plot for the incidence of (A) major adverse cardiovascular events at 24 weeks and (B) all thrombolysis in myocardial infarction major, minor, and clinically relevant bleeding events in all patients and in patients subdivided on the basis of CYP2C19 genotype. CI, confidence interval; EM, extensive metabolizer; HR, hazard ratio; IM, intermediate metabolizer; PGx, pharmacogenomic analysis set; PM, poor metabolizer.
Table 1Incidence of major adverse cardiovascular events and its components through to week 24 in patients subdivided on the basis of CYP2C19 variants (pharmacogenomic and full analysis set).
The incidences of all non-coronary artery bypass graft (CABG)-related bleeding events and spontaneous bleeding in all patients, EM patients, and IM + PM patients are compared between the prasugrel and clopidogrel groups in Table 2.
Table 2Incidence of non-coronary artery bypass graft-related bleeding events in patients subdivided on the basis of CYP2C19 variants (pharmacogenomic and safety analysis set).
In the pharmacogenomic analysis set (n = 773), the incidence of non-CABG-related major, minor, or clinically relevant bleeding events was 7.2% (28/390) in the prasugrel group and 9.4% (36/383) in the clopidogrel group. Among EM patients, the incidence of major bleeding events was 2.6% (4/153) in the prasugrel group and 1.5% (2/135) in the clopidogrel group. The incidence of major spontaneous bleeding events was similar in both groups. The incidence of major or minor bleeding events was 4.6% (7/153) in the prasugrel group and 3.7% (5/135) in the clopidogrel group, but the incidence of spontaneous major or minor bleeding events was 0.7% (1/153) in the prasugrel group and 1.5% (2/135) in the clopidogrel group. The incidence of overall bleeding, major, minor, or clinically relevant bleeding, and bleeding events leading to discontinuation was similar in both groups.
Among IM + PM patients, the incidence of major bleeding was 0.4% (1/237) in the prasugrel group and 1.2% (3/248) in the clopidogrel group. The incidence of major or minor bleeding events was 3.4% (8/237) in the prasugrel group and 3.2% (8/248) in the clopidogrel group. The incidence of non-CABG-related major, minor, or clinically relevant bleeding was 5.9% (14/237) in the prasugrel group and 9.3% (23/248) in the clopidogrel group. The incidence of overall bleeding events (50.2% vs. 31.9%; HR: 1.80; 95% CI: 1.35–2.39) was significantly greater in the prasugrel group than in the clopidogrel group, but the incidence of spontaneous bleeding events (14.3% vs. 13.7%; HR: 1.03; 95% CI: 0.64–1.65) was similar in both treatment groups (Table 2).
The incidences of spontaneous bleeding events were generally similar between the prasugrel and clopidogrel groups irrespective of the CYP2C19 status, except for the incidence of major, minor, or clinically relevant bleeding events in all patients, being 3.8% in the prasugrel group and 7.0% in the clopidogrel group (HR: 0.54; 95% CI: 0.29–1.02), and the incidence of clinically relevant bleeding, being 2.8% in the prasugrel group and 6.0% in the clopidogrel group (HR: 0.47; 95% CI: 0.23–0.96).
Discussion
In this analysis of the PRASFIT-ACS study results, we found that the presence of reduced-function CYP2C19 genotypes, characterized as IM + PM, did not substantially affect the efficacy and safety of prasugrel relative to EM patients. Prasugrel at a LD of 20 mg achieved significantly greater platelet inhibition than did clopidogrel at a LD 300 mg over the first 12 h in EM patients and in IM + PM patients. Beyond 4 weeks after PCI, platelet inhibition was comparable between the two treatment groups in EM patients, but was significantly greater in the prasugrel group than in the clopidogrel group in IM + PM patients. Among clopidogrel-treated patients, the level of platelet inhibition was significantly lower in IM + PM patients than in EM patients, but platelet inhibition was comparable between clopidogrel-treated EM patients and prasugrel-treated IM + PM patients from 4 weeks after PCI (data not shown).
Regarding the impact of CYP2C19 alleles, in TRITON-TIMI 38, clopidogrel-treated patients with reduced-function CYP2C19 alleles (IM + PM) displayed weaker platelet inhibition and a higher rate of MACE than did patients with normal-function CYP2C19 alleles [
]. In PRASFIT-ACS, the incidence of MACE was similar between the prasugrel group and the clopidogrel group among EM patients, and numerically lower in the prasugrel group than in the clopidogrel group among IM + PM patients. The most frequent type of MACE in PRASFIT-ACS was peri-procedural MI, with an incidence of 5.3% in the prasugrel group and 8.1% in the clopidogrel group for all patients; the incidences were 6.9% in the prasugrel group and 9.4% in the clopidogrel group in the pharmacogenomics analysis set. It was reported that the peak creatine kinase myocardial band (CK-MB) value at the onset of MI is related to the post-event mortality rate [
]. In TRITON-TIMI 38, the incidence of major MI associated with a peak CK-MB value of ≥5 times the normal upper limit was significantly lower in the prasugrel group than in the clopidogrel group (HR: 0.74; 95% CI: 0.64–0.86) [
Effect of the novel thienopyridine prasugrel compared with clopidogrel on spontaneous and procedural myocardial infarction in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38: an application of the classification system from the universal definition of myocardial infarction.
]. Accordingly, we compared the incidence of peri-procedural MI according to the peak CK-MB value in patients of each CYP2C19 genotype. In patients with peak CK-MB values ≥5 or ≥10 times the upper limit of normal, the incidence of peri-procedural MI in EM and IM + PM patients was numerically lower in the prasugrel group than in the clopidogrel group (Table 3). Because the effect of inhibition of platelet aggregation in the early period after the LD was greater in EM and IM + PM in the prasugrel group than in the clopidogrel group, the greater level of platelet inhibition was possibly related to the prevention of severe peri-procedural MI. However, because these outcomes are derived from post hoc sub-analyses and the sample size was limited, further studies in greater numbers of patients are needed to elucidate the relationships between CYP2C19 and efficacy events.
Table 3Incidence of peri-procedural myocardial infarction stratified by the peak creatine kinase myocardial band value in patients subdivided on the basis of CYP2C19 variants (pharmacogenomic analysis set).
Peak CK-MB value
EM
IM + PM
Prasugrel (n = 153)
Clopidogrel (n = 135)
RR (95% CI)
Prasugrel (n = 237)
Clopidogrel (n = 248)
RR (95% CI)
All patients
14 (9.2)
13 (9.6)
0.95 (0.46–1.95)
13 (5.5)
22 (8.9)
0.62 (0.32–1.20)
3 to <5 × ULN
4 (2.6)
1 (0.7)
3.53 (0.40–31.19)
2 (0.8)
3 (1.2)
0.70 (0.12–4.14)
5 to <10 × ULN
4 (2.6)
3 (2.2)
1.18 (0.27–5.16)
3 (1.3)
6 (2.4)
0.52 (0.13–2.07)
≥5 × ULN
10 (6.5)
12 (8.9)
0.74 (0.33–1.65)
11 (4.6)
19 (7.7)
0.61 (0.29–1.25)
≥10 × ULN
6 (3.9)
9 (6.7)
0.59 (0.21–1.61)
8 (3.4)
13 (5.2)
0.64 (0.27–1.53)
Peri-procedural myocardial infarctions were adjudicated according to the 3rd Universal Definition of Myocardial Infarction.
The incidence of non-CABG-related major bleeding and the incidence of major, minor, or clinically relevant bleeding were almost the same in the prasugrel and clopidogrel groups in all CYP2C19 phenotypes. In TRITON-TIMI 38, the incidence of major and minor bleeding was numerically higher in the prasugrel-treated patients with reduced-function CYP2C19 alleles (i.e. IM + PM patients) than in noncarriers [
]. However, this trend was not observed in the PRASFIT-ACS study. Based on the TRITON-TIMI 38 results, we used an adjusted dosing regimen for Japanese patients to minimize the risk of bleeding irrespective of the CYP2C19 genotype. Although the incidence of overall bleeding events in IM + PM patients was significantly greater in the prasugrel group than in the clopidogrel group, the incidence of spontaneous bleeding events was similar in both treatment groups. In the prasugrel group, the incidence of overall bleeding in IM + PM patients was similar to that in EM patients (50.2% vs. 47.7%; HR: 1.03; 95% CI: 0.77–1.38). These results indicate that prasugrel with a LD/MD of 20/3.75 mg showed consistent efficacy and safety regardless of the CYP2C19 phenotype in Japanese ACS patients. In the clopidogrel group, the incidence of overall bleeding in EM patients was similar to that in the prasugrel group, but the incidence of overall bleeding in IM + PM patients was significantly lower than that in EM patients (31.9% vs. 45.2%; HR: 0.66; 95% CI: 0.47–0.92). Based on these results, the efficacy and safety of prasugrel are not influenced by the CYP2C19 genotype. Considering that genetic testing may not be available at all institutions, and because many patients may be unwilling to undergo genetic testing, our results suggest that prasugrel could be suitable for all Japanese ACS patients undergoing PCI, irrespective of the CYP2C19 phenotype. Taken together, these data support the clinical use of prasugrel in Japanese ACS patients, and suggest that its efficacy and safety are not influenced by the CYP2C19 genotype. These data also highlight the potential for using prasugrel as an alternative to clopidogrel.
Some limitations warrant mention. First, only genetic variants of CYP2C19 were assessed in this study, however some patients may have polymorphisms in other enzymes that could impair the responses to prasugrel. Second, only about one-half of the patients who participated in PRASFIT-ACS underwent genetic testing, reducing the statistical power of the analyses. Finally, this study was not specifically powered to detect differences in the incidence of MACE or bleeding events among patients subdivided on the basis of CYP2C19 genetic variants.
Conclusions
In conclusion, prasugrel at a LD/MD of 20/3.75 mg had stable antiplatelet effects, irrespective of the CYP2C19 genotype, after PCI in Japanese ACS patients. Although the incidence of MACE was 9.3% in the prasugrel group and 12.5% in the clopidogrel group (HR: 0.78; 95% CI: 0.45–1.35) in IM + PM patients, there were no significant differences in terms of the incidences of MACE and clinically relevant bleeding between the two treatments among patients of each CYP2C19 phenotype. Further studies are needed to assess the impact of genetic variants of cytochrome P450 and other enzymes on the efficacy and safety of prasugrel.
Funding
This study was funded by Daiichi Sankyo, Co., Ltd.
Disclosure
The authors declare the following interests: Hisao Ogawa has received honoraria from AstraZeneca K.K., Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Daiichi Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Eisai Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K., Pfizer Japan Inc., Sanofi K.K., and Takeda Pharmaceutical Co., Ltd., clinical research funding from Daiichi Sankyo Co., Ltd., and other research funding from Astellas Pharma Inc., AstraZeneca K.K., Boehringer Ingelheim Japan, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., and Takeda Pharmaceutical Co., Ltd.; Takaaki Isshiki has received honoraria from AstraZeneca K.K., Daiichi Sankyo Co., Ltd., Otsuka Pharmaceutical Co., Ltd, and Sanofi K.K.; Takeshi Kimura has received honoraria, clinical research funding, and other research funding from Daiichi Sankyo Co., Ltd. and Sanofi K.K.; Hiroyoshi Yokoi has no conflicts of interest to declare; Shinsuke Nanto has received honoraria from Daiichi Sankyo Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Medtronic, and Sanofi K.K., fees for promotional services from Takeda Pharmaceutical Co., Ltd. and Otsuka Pharmaceutical Co., Ltd., clinical research funding from Abbott Vascular Japan and Terumo, other research funding from Boston Scientific Japan, Medtronic, St. Jude Medical Japan, Abbott Vascular Japan, Daiichi Sankyo Co., Ltd., and Sanofi K.K., and an endowment from Terumo; Morimasa Takayama is a clinical advisor for Abbott Vascular Japan and Kaneka Medics Co., Ltd., and has received honoraria from Daiichi Sankyo Co., Ltd.; Kazuo Kitagawa has received honoraria from Sanofi K.K., and other research funding from Daiichi Sankyo, Co., Ltd., Boehringer Ingelheim Japan, Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Sanofi K.K., and Mitsubishi Tanabe Pharma Corporation; Masakatsu Nishikawa has received honoraria from Daiichi Sankyo Co., Ltd. and Otsuka Pharmaceutical Co., Ltd., and other research funding from Otsuka Pharmaceutical Co.; Shunichi Miyazaki has received other research funding from MSD K.K.; Yasuo Ikeda has received honoraria from Daiichi Sankyo Co., Ltd., and research grants from Daiichi Sankyo Co., Ltd. and Sanofi K.K.; Masato Nakamura has received honoraria from Daiichi Sankyo Co., Ltd., Sanofi K.K., and AstraZeneca K.K.; Yuko Tanaka is an employee of Daiichi Sankyo Co., Ltd and undertook the data processing and statistical analysis; Shigeru Saito is a medical advisor for Terumo and has received honoraria from Abbot Vascular Japan, Boston Scientific Japan, and Medtronic.
Acknowledgments
The authors deeply appreciate the contributions of all the investigators and other clinical/research staff involved in the present study. The authors also thank Nicholas D. Smith, PhD, for providing medical writing support.
Appendix A. Supplementary data
The following are the supplementary data to this article:
CYP2C19*2 and *17 alleles have a significant impact on platelet response and bleeding risk in patients treated with prasugrel after acute coronary syndrome.
Effects of coexisting polymorphisms of CYP2C19 and P2Y12 on clopidogrel responsiveness and clinical outcome in patients with acute coronary syndromes undergoing stent-based coronary intervention.
Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.
Impact of CYP2C19 genetic testing on provider prescribing patterns for antiplatelet therapy after acute coronary syndromes and percutaneous coronary intervention.
Effect of the novel thienopyridine prasugrel compared with clopidogrel on spontaneous and procedural myocardial infarction in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38: an application of the classification system from the universal definition of myocardial infarction.
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