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International Journal of Cardiology 182 (2015) 541–548

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Optimal cutoff value of P2Y12 reaction units to prevent major adverse cardiovascular events in the acute periprocedural period: Post-hoc analysis of the randomized PRASFIT-ACS study☆,☆☆ Masato Nakamura a,⁎, Takaaki Isshiki b, Takeshi Kimura c, Hisao Ogawa d, Hiroyoshi Yokoi e, Shinsuke Nanto f, Morimasa Takayama g, Kazuo Kitagawa h, Yasuo Ikeda i, Shigeru Saito j a

Division of Cardiovascular Medicine, Ohashi Medical Center, Toho University, Tokyo, Japan Division of Cardiology, Teikyo University Hospital, Tokyo, Japan c Graduate School of Medicine, Kyoto University, Kyoto, Japan d Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, and National Cerebral and Cardiovascular Center, Suita, Japan e Fukuoka Sanno Hospital, Fukuoka, and International University of Health and Welfare, Ohtawara, Japan f Superintendent, Nishinomiya Hospital Affairs, Nishinomiya Municipal Central Hospital, Nishinomiya, Japan g Sakakibara Heart Institute, Tokyo, Japan h Department of Neurology, Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan i Life Science & Medical Bioscience, Faculty of Science and Engineering, Waseda University, Tokyo, Japan j Division of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan b

a r t i c l e

i n f o

Article history: Received 4 September 2014 Received in revised form 15 December 2014 Accepted 4 January 2015 Available online 8 January 2015 Keywords: Prasugrel Acute coronary syndrome Clopidogrel Major adverse cardiovascular event Platelet reactivity CYP2C19

a b s t r a c t Background: Few studies have examined the effects of on-treatment platelet reactivity on the risk of major adverse cardiovascular events (MACE). We aimed to determine the optimal cutoff value of P2Y12 reaction units (PRUs) to prevent MACE occurring within 3 days after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). Methods: We performed post-hoc analyses of 1363 patients enrolled in PRASFIT-ACS, which compared the effects of a prasugrel regimen adjusted for Japanese patients (loading dose/maintenance dose: 20 mg/3.75 mg) with those of clopidogrel (300 mg/75 mg) on MACE and bleeding events for 24–48 weeks after PCI in ACS patients. PRU was serially measured using the VerifyNow® P2Y12 assay and we assessed the relationship between PRU and MACE. Results: Receiver operating characteristic curve analysis showed that PRU ≤262 at 5–12 h after ADP receptor antagonist loading was the optimal cutoff value for preventing MACE at up to 3 days after PCI. The incidences of MACE were 5.2% and 10.8% in patients with PRU ≤262 or N 262, respectively (odds ratio 0.50, 95% confidence interval 0.25–0.99, p b 0.01). Significantly more prasugrel-treated patients had lower on-treatment platelet reactivity (defined as PRU ≤ 262) compared with clopidogrel-treated patients (79.9% vs. 30.4%, p b 0.0001). Similar differences were observed between the prasugrel and clopidogrel groups for patients with normal or reducedfunction CYP2C19 alleles. Conclusions: The optimal PRU cutoff value for preventing MACE was 262 in Japanese ACS patients. Prasugrel rapidly reduced PRU with a large proportion of patients having low on-treatment platelet reactivity. © 2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

☆ PRASFIT-ACS: PRASugrel compared with clopidogrel For Japanese patIenTs with Acute Coronary Syndrome undergoing percutaneous coronary intervention (JapicCTI101339). ☆☆ Trial registration number: JapicCTI-101339 (Japan Pharmaceutical Information Center Clinical Trials Information, http://www.clinicaltrials.jp/user/cteSearch.jsp). ⁎ Corresponding author at: Toho University, Ohashi Medical Center, Division of Cardiovascular Medicine, 2-17-6 Ohashi, Meguro, Tokyo 153-8515, Japan. E-mail address: [email protected] (M. Nakamura).

Dual antiplatelet treatment with aspirin and clopidogrel is widely recommended as a treatment for acute coronary syndrome [1,2]. However, clopidogrel shows a delayed onset of action and its pharmacodynamic effect may be insufficient to adequately suppress platelet aggregation to prevent thrombotic events [3]. Furthermore, clopidogrel exhibits pharmacodynamic variability between individuals, mainly because of genetic variations in cytochrome P450 (CYP) 2C19 [4–6]. Therefore, some clopidogrel-treated patients exhibit high on-

http://dx.doi.org/10.1016/j.ijcard.2015.01.026 0167-5273/© 2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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M. Nakamura et al. / International Journal of Cardiology 182 (2015) 541–548

treatment platelet reactivity (HPR), which is associated with increased risk of ischemic events such as stent thrombosis [7–10]. Thus, newer P2Y12 receptor antagonists with more potent and quicker pharmacological effects have been developed. These newer agents, namely prasugrel and ticagrelor, showed superiority over clopidogrel in clinical trials [11, 12], although the stronger antiplatelet effects of prasugrel and ticagrelor were associated with a greater risk of non-coronary artery bypass graftrelated major bleeding, partly offsetting the clinical benefits of these drugs in both trials. A concern about prasugrel has arisen in that the lower body weight of Japanese populations may increase their bleeding risk relative to that in Western populations. Therefore, we examined the clinical efficacy of a prasugrel regimen optimized for Japanese patients (loading dose [LD]/ maintenance dose [MD]: 20 mg/3.75 mg) used in an earlier Japanese phase II trial (unpublished data). This dose was selected based on the results of a phase I study using LD/MD of 10/2.5 mg, 15/3.75 mg, and 20/5 mg [13]. This regimen was associated with a low incidence of major adverse cardiac events (MACE) without an increased risk of clinically serious bleeding in Japanese ACS patients enrolled in a multicenter randomized controlled study (PRASFIT-ACS: PRASugrel compared with clopidogrel For Japanese patIenTs with Acute Coronary Syndrome undergoing percutaneous coronary intervention) [14]. The incidence of MACE within 3 days after percutaneous coronary intervention (PCI) in PRASFIT-ACS was 5.3% in the prasugrel group and 8.3% in the clopidogrel group (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.41–0.95, p = 0.026; full analysis set: 1363 patients). It was postulated that the point of care approach for ACS patients might help to reduce both ischemic and bleeding events, as studies assessing the potential cutoff value for platelet inhibition observed outcomes that tended to be inconsistent among prior studies [15–17]. In addition, observational studies demonstrated a relationship between adverse events and HPR [15]. The results of randomized trials that investigated the value of a personalized antiplatelet treatment regimen based on platelet function did not support the point of care approach [16,17]. These inconsistencies may be explained by the fact that the patients enrolled in randomized controlled studies were generally limited to patients with stable coronary artery disease undergoing elective PCI. In trials addressing the efficacy of different antiplatelet regimens for ACS patients, a division in the Kaplan–Meier curves of cumulative MACE was observed immediately after randomization and the curves continued to separate over time, which suggests that more potent antiplatelet therapies confer ongoing benefits on MACE [11,12,14]. This finding demonstrates the efficacy of potent and rapidly acting antiplatelet

regimens. However, the relationship between MACE and platelet function inhibition, in terms of P2Y12 reaction units (PRUs), during the acute phase after the LD has not been comprehensively assessed. Therefore, we conducted a post-hoc analysis of the results of the PRASFIT-ACS study to investigate the association between platelet reactivity in the acute, early phase after the LD and adverse cardiac events occurring up to 3 days after PCI in Japanese ACS patients. We chose the acute period of treatment (up to 3 days after PCI) because the majority of cardiovascular events occurred in this period and because of the ease of monitoring the platelet inhibition using point-of-care assays. 2. Methods 2.1. Study design PRASFIT-ACS was a multicenter, randomized, double-blind, double-dummy, two-way parallel-group study performed at 162 sites in Japan between December 2010 and June 2012 (Appendix A) [14]. The database was locked on September 2012. The patients were treated for 24–48 weeks with the allocated study drug, after which they were followed up for a further 14 days to detect possible safety issues or other events occurring after completing treatment. Eligible patients were randomized (1:1) to either prasugrel or clopidogrel after providing written informed consent. The LD of prasugrel (20 mg) or clopidogrel (300 mg) was usually administered before PCI, but could be administered up to 1 h after the patient left the cardiac catheter laboratory in urgent cases (urgent cases: 29.2%). After PCI, the patients received the MD of prasugrel (3.75 mg) or clopidogrel (75 mg) once daily after breakfast during the treatment period. Treatment was intended to continue for 48 weeks, but could be completed at 24 weeks if the investigator deemed it appropriate for the individual patient, taking into account the stent type and the recommended duration of thienopyridine administration, as stated in the package inserts. The concomitant use of antiplatelet drugs (other than aspirin), anticoagulant drugs, thrombolytic drugs, or acidic non-steroidal anti-inflammatory drugs was prohibited. The CYP2C19 genotype was assessed as described below. The study was conducted in accordance with the Declaration of Helsinki in compliance with Good Clinical Practice. The study was approved by the institutional review boards at all of the participating institutions. PRASFIT-ACS was registered on the Japan Pharmaceutical Information Center Clinical Trials Information database (http://www.clinicaltrials.jp/user/cteSearch.jsp) with the identifier JapicCTI-101339. 2.2. Patients The enrollment process and eligibility criteria are reported in more detail elsewhere [14]. In brief, patients were eligible if they satisfied all of the following criteria: presenting with chest discomfort or ischemic symptoms lasting ≥10 min within 72 h before randomization, myocardial ischemia (confirmed by electrocardiography), or myocardial necrosis (confirmed by changes in cardiac biomarkers). Patients with a history of intracranial bleeding or ischemic stroke/transient ischemic attack, current or predisposition to hemorrhagic disease, or poorly controlled hypertension were excluded. Platelet reactivity data were obtained in 1256/1363 patients enrolled in PRASFIT-ACS. Of these patients, platelet function was measured 5–12 h after the LD (mean: 7 h 29 min; median: 6 h 54 min) in 660 patients. These patients were included in analyses of platelet inhibition and MACE in this post-hoc analysis.

Fig. 1. Time-course of platelet reactivity determined by the VerifyNow® P2Y12 assay after the loading dose and during the maintenance dose phase. *p b 0.0001 vs. clopidogrel by repeated measures ANOVA; the least square mean in the model was compared among groups at each time point, and time points showing a significant difference are marked with an asterisk. LD: loading dose; MD: maintenance dose; PRU: platelet reactivity unit.

M. Nakamura et al. / International Journal of Cardiology 182 (2015) 541–548 2.3. Primary endpoint The primary efficacy endpoint (i.e., MACE) was a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal ischemic stroke. Non-fatal myocardial infarction was defined as events fulfilling at least one of the following three criteria. First, in patients with normal creatine kinase-MB before PCI/coronary artery bypass grafting, creatine kinase-MB had to be greater than (a) three times the upper limit of normal in two samples obtained after PCI, or greater than five times the upper limit of normal in one sample obtained b48 h after PCI/coronary artery bypass grafting, or (b) 10 times the upper limit of normal in one sample obtained b48 h after coronary artery bypass grafting. Creatine kinase-MB before PCI/coronary artery bypass grafting had to show a transient decrease with re-elevation at least 1.5 times the upper limit of normal, and also satisfy (a) or (b). Second, 48 h after PCI, creatine kinase-MB or troponin had to be greater than the upper limit of normal, and accompanied by one of the following: c) sustained ischemic chest pain, d) hemodynamic decompensation, or e) ST elevation or depression of ≥0.1 mV. Third, abnormal Q waves had to persist for N0.04 s. The other efficacy endpoints were assessed by calculating the incidence of cardiovascular deaths, all-cause death, nonfatal myocardial infarction, non-fatal stroke with/without ischemia, myocardial ischemia requiring rehospitalization, revascularization, and stent thrombosis defined as definite or probable according to Academic Research Consortium criteria [18].

3.2. Characteristics of patients included in the analyses of PRU to avoid MACE Table 1 shows the characteristics of 660 patients (prasugrel, 328; clopidogrel, 332) in whom PRU was measured at 5–12 h after the LD. There were some differences in the clinical presentation (prevalences of unstable angina and non-ST-elevation myocardial infarction) between the two treatment groups, but other characteristics were similar in both groups. Overall, 51/660 patients (7.7%) experienced MACE. The incidence of MACE was 6.1% (20/328) in the prasugrel group and 9.3% (31/332) in

Table 1 Characteristics of patients in whom platelet reactivity was assessed at 5–12 h after the loading dose.

2.4. Platelet aggregation study The pharmacodynamics of prasugrel and clopidogrel were assessed using the VerifyNow® P2Y12 assay (Accumetrics, San Diego, California) in patients who permitted blood collection. VerifyNow® P2Y12 baseline reactivity, PRU, and percent inhibition of P2Y12 were assessed. PRU was measured at baseline, in the LD phase (2–4, and 5–12 h after the LD), and during the MD phase (at 4, 12, 24, 36, and 48 weeks after PCI). Whole-blood samples (approximately 2 ml) were collected from non-fasted patients in tubes containing 3.2% sodium citrate. The blood samples were left for 10 min up to 4 h before measurement. Whole-blood samples were used and measurements were performed according to the manufacturer's instructions. 2.5. Assessment of the CYP2C19 genotype The genotypes of the CYP2C19*2 and *3 alleles, which markedly decrease CYP2C19 enzyme activity, were determined using the TaqMan™ Drug Metabolism Genotyping Assays in 220 prasugrel-treated patients and 211 clopidogrel-treated patients who gave informed consent for these tests. The genotypes were classified into three phenotypes: extensive metabolizers (EM) with normal function alleles (CYP2C19*1/*1), intermediate metabolizers (IM) with one reduced-function allele (*1/*2, *1/*3), and poor metabolizers (PM) with two reduced-function alleles (*2/*2, *2/*3, *3/*3). 2.6. Statistical methods For subject background characteristics, we compared categorical outcomes using the χ2 or Fisher's exact tests and continuous variables using the Student's t test. Differences between groups in terms of the time-course of platelet reactivity and the effects of CYP2C19 alleles on platelet reactivity were determined by repeated measures ANOVA with comparison of the least square means. The proportions of patients with platelet reactivity units below the cutoff value were compared using the χ2 test. Results are presented as means (standard deviation). Receiver operating characteristic analyses were conducted to determine the usefulness of PRU for distinguishing between patients with and without ischemic cardiovascular events in the periprocedural period (i.e., up to 3 days after PCI). The optimal cutoff value was the on-treatment PRU that provided the greatest sum of sensitivity and specificity. After applying the proportional hazard assumption, the Cox regression model was used for univariate and multivariate analyses to identify risk factors for MACE occurring within 3 days after PCI, and to adjust for potential confounders associated with MACE (multivessel lesions, hypertension, dyslipidemia, current smoker, prior myocardial infarction, and treatment received). All statistical analyses were performed using SAS version 9.2 (SAS Institute, Cary, North Carolina).

3. Results 3.1. PRU after administration of prasugrel or clopidogrel in the overall study population As shown in Fig. 1, PRU measured using the VerifyNow® P2Y12 assay at 2–4 h (p b 0.0001) and 5–12 h (p b 0.0001) after the LD was significantly lower in the prasugrel group than in the clopidogrel group. This effect of prasugrel persisted into the MD treatment period at 4, 12, 24, 36, and 48 weeks (all, p b 0.0001). The LD of clopidogrel did not reduce PRU at up to 12 h after administration, but 4 weeks of treatment with the MD did reduce PRU. However, the reduction in PRU after 4 weeks of treatment was smaller in the clopidogrel group than in the prasugrel group.

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Females Age, years ≥75 years Body weight, kg ≤50 kg ≤60 kg BMI, kg/m2 Current smoker, yes Cardiac conditions UA NSTEMI STEMI CrCL (ml/min) Eligible, n ≥60 ml/min b60 ml/min Clinically relevant disorders Hypertension Dyslipidemia Diabetes mellitus Concomitant therapy Proton pump inhibitor Statin Ca channel blocker ACEI ARB β-Blocker First revascularization PCI CABG None Treatment vessel Single Multiple No PCI Type of stent BMS DES Timing of LD Before PCI During PCI After PCI No PCI CYP2C19 phenotype Eligible, n Normal function (EM) Reduced function IM PM

Prasugrel (n = 328)

Clopidogrel (n = 332)

All patients (n = 660)

χ2 test (*t-Test)

60 (18.3) 65.2 ± 11.7 78 (23.8) 64.8 ± 12.2 34 (10.4) 120 (36.6) 24.2 ± 3.4 136 (41.5)

67 (20.2) 65.6 ± 11.3 81 (24.4) 64.4 ± 11.4 42 (12.7) 119 (35.8) 24.4 ± 3.3 130 (39.2)

127 (19.2) 65.4 ± 11.5 159 (24.1) 64.6 ± 11.8 76 (11.5) 239 (36.2) 24.3 ± 3.4 266 (40.3)

0.5384 0.6461* 0.8529 0.6035* 0.3579 0.8428 0.5688* 0.0774 0.0143

70 (21.3) 81 (24.7) 176 (53.7)

44 (13.3) 107 (32.2) 181 (54.5)

114 (17.3) 188 (28.5) 357 (54.1)

298 236 (79.2) 62 (20.8)

302 240 (79.5) 62 (20.5)

600 476 (79.3) 124 (20.7)

238 (72.6) 255 (77.7) 129 (39.3)

251 (75.6) 250 (75.3) 116 (34.9)

489 (74.1) 505 (76.5) 245 (37.1)

0.3726 0.4592 0.2432

145 (44.2) 175 (53.4) 86 (26.2) 66 (20.1) 92 (28.0) 63 (19.2)

149 (44.9) 161 (48.5) 70 (21.1) 42 (12.7) 86 (25.9) 45 (13.6)

294 (44.5) 336 (50.9) 156 (23.6) 108 (16.4) 178 (27.0) 108 (16.4)

0.8621 0.2118 0.1205 0.0095 0.5347 0.0497 0.9759

324 (98.8) 2 (0.6) 3 (0.9)

330 (99.4) 1 (0.3) 1 (0.3)

654 (99.1) 3 (0.5) 4 (0.6)

221 (67.4) 103 (31.4) 4 (1.2)

233 (70.2) 97 (29.2) 2 (0.6)

454 (68.8) 200 (30.3) 6 (0.9)

171 (53.3) 152 (47.4)

180 (55.4) 147 (45.2)

351 (54.3) 299 (46.3)

196 (59.7) 19 (5.8) 109 (33.2) 4 (1.2)

202 (60.8) 26 (7.8) 102 (30.7) 2 (0.6)

398 (60.3) 45 (6.8) 211 (32.0) 6 (0.9)

220 87 (39.5) 133 (60.5) 92 (41.8) 41 (18.6)

211 80 (37.9) 131 (62.1) 92 (43.6) 39 (19.5)

431 167 (38.7) 264 (61.3) 184 (42.7) 80 (18.6)

0.9965

0.5656

0.5754

0.6943

0.9252

Values are means ± standard deviation or n (%). BMI: body mass index; UA: unstable angina; NSTEMI: non-ST-elevation myocardial infarction; STEMI: ST-elevation myocardial infarction; CrCL: creatinine clearance (estimated using the Cockcroft–Gault formula); Ca: calcium; ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; PCI: percutaneous coronary intervention; CABG: coronary artery bypass graft; BMS: bare metal stent; DES: drug-eluting stent; LD: loading dose; EM: extensive metabolizers; IM: intermediate metabolizers; PM: poor metabolizers.

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the clopidogrel group (risk reduction 38%, odds ratio [OR] 0.62, 95% CI 0.34–1.12). 3.3. Association between platelet reactivity and MACE We plotted the PRU measured at 5–12 h after the LD according to the study drug received (Fig. 2A), and in all patients with or without MACE (Fig. 2B). PRU values were higher in patients with MACE than in patients without MACE (Fig. 2B). Receiver operating characteristic curve analysis was performed using PRU for on-treatment platelet reactivity in all patients to distinguish between patients with or without MACE (Fig. 3). The area under the curve was 0.58 (95% CI 0.50–0.65) and PRU of 262 was the optimal cutoff value for preventing MACE after PCI. The overall incidence of MACE through to day 3 was 5.2% (19/363) in patients with PRU ≤262 and 10.8% in patients with PRU N 262 (risk reduction 0.5, OR 0.50, 95% CI: 0.25–0.99, p b 0.01) (Table 2; Fig. 4, inset). The values at week 24 in patients with PRU ≤262 and patients with PRU N262 were 8.8% (32/328) and 15.5% (46/297), respectively, corresponding to a risk reduction of 49% (OR 0.51, 95% CI 0.29–0.90) (Fig. 4). PRU was ≤ 262 in significantly more prasugrel-treated patients than clopidogrel-treated patients (79.9% vs. 30.4%, p b 0.0001; Fig. 5). However, the ORs for MACE in patients with PRU ≤262 vs. PRU N262 were similar in both groups (Table 2). In multivariate Cox regression analysis (Table 3), PRU N262 was independently associated with a higher risk of MACE (HR 2.02, 95% CI 1.05–3.90, p b 0.05) after adjusting for confounding factors that were associated with MACE in univariate analyses. In this analysis, the presence of multivessel disease was also a significant risk factor for MACE (p b 0.05). 3.4. Effects of CYP2C19 polymorphisms on changes in PRU and the proportions of patients with PRU ≤262 Only 18.6% of patients with known CYP2C19 status were classified as PM (Table 1). Therefore, we combined the PM and IM groups to provide a larger group of patients with reduced-function CYP2C19 polymorphisms. This allowed us to increase the reliability of statistical analyses by comparing patients with normal or reduced-function CYP2C19 polymorphisms. The proportion of patients with PRU ≤262 was significantly higher in the prasugrel group than in the clopidogrel group (p b 0.0001). Similar differences were observed between the prasugrel and clopidogrel groups for patients with normal (85.1% vs. 45.0%, p b 0.0001) or reduced-function (76.7% vs. 27.5%, p b 0.0001) CYP2C19 alleles. In the clopidogrel group, the proportion of patients with PRU ≤ 262 was significantly (p b 0.01) smaller among patients with reduced-function alleles than among patients with normal function alleles (Fig. 6). The reduction in PRU in the acute phase after PCI was

Fig. 3. Receiver operating characteristic curve for platelet reactivity units determined using the VerifyNow® P2Y12 assay. AUC: area under the curve; CI: confidence interval.

significantly greater in the prasugrel group than in the clopidogrel group irrespective of CYP2C19 status (p b 0.0001) (Fig. 7). The prasugrel MD achieved significantly greater reductions in PRU than did the clopidogrel MD among patients with reduced-function CYP2C19 alleles. 4. Discussion This post-hoc analysis of the PRASFIT-ACS study had three main findings. 1) Platelet reactivity at 5–12 h after the LD of clopidogrel or prasugrel was associated with MACE up to 3 days after PCI in ACS patients. 2) PRU ≤262 was a clinically relevant cutoff value for preventing MACE after PCI and the proportion of non-responders (PRU N262) was significantly lower in the prasugrel group than in the clopidogrel group (20.1% vs. 69.6%, p b 0.0001). 3) Prasugrel was associated with a higher achievement rate of PRU ≤262 compared with clopidogrel in patients with normal or reduced-function CYP2C19 alleles. 4.1. Association between platelet reactivity and adverse events Numerous reports have described an association between platelet reactivity and ischemic events. For example, Marcucci et al. [15]

Fig. 2. Platelet reactivity determined by the VerifyNow® P2Y12 assay at 5–12 h after administration of the loading dose. (A) All patients treated with prasugrel or clopidogrel. (B) All patients with or without major adverse cardiovascular events within 3 days after percutaneous coronary intervention. MACE: major adverse cardiovascular events; PRU: platelet reactivity unit.


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Table 2 Incidence of major adverse cardiovascular events in patients divided by platelet reactivity.

All patients PRU N262b CV deathc MIc PRU ≤262b MIc OR 95% CI p value

Number of patients

Patients with MACEa

Prasugrel

Clopidogrel

660 297

51 (7.7%) 32 (10.8%) 2/297 (0.7%) 30/297 (10.1%) 19 (5.2%) 19/363 (5.2%) 0.497 0.249–0.989 b0.01

328 6/66 (9.1%) 0/66 (0%) 6/66 (9.1%) 14/262 (5.3%) 14/262 (5.3%) 0.559 0.205–1.523 0.232

332 26/231 (11.3%) 2/231 (0.9%) 24/231 (10.4%) 5/101 (5.0%) 5/101 (5.0%) 0.445 0.163–1.218 0.085

363

CI: confidence interval; MACE: major adverse cardiovascular events; MI: myocardial infarction; PRU: platelet reactivity unit; OR: odds ratio; CV: cardiovascular death. a MACE occurring within 3 days after percutaneous coronary intervention. b PRU at 5–12 h after treatment was determined using the VerifyNow® P2Y12 assay. c n (%) of patients whose event was classified as MI or CV death.

reported that PRU within 24 h after the administration of double-dose clopidogrel was associated with the incidence of ischemic events up to 12 months after coronary stenting, and that PRU ≥240 was a significant and independent predictor of ischemic events. Cuisset et al. [19] reported that HPR on clopidogrel was a marker for increased periprocedural myocardial infarction risk in patients with non-ST-elevation myocardial infarction. Parodi et al. [20] reported that the incidence of the primary endpoint at 2 years was higher in ACS patients with HPR (14.6% vs 8.7%, p = 0.003). Our post-hoc analysis also showed an association between PRU at 5–12 h after the LD and MACE occurring up to 3 days after PCI in ACS patients. By contrast, three recent randomized trials failed to demonstrate the utility of the point of care approach in mainly stable coronary artery disease patients with HPR treated with clopidogrel [16,17,21]. The largest study, ADAPT-DES (Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents) [10], noted that a PRU N208 was independently associated with the risk of stent thrombosis within 30 days after PCI with drug-eluting stents in ACS patients (adjusted HR 3.91, p = 0.005), whereas no association was found in nonACS patients (adjusted HR 1.49, p = 0.59). These inconsistent outcomes

might be partly explained by enrollment of low-risk patients, and the studies were probably underpowered to detect significant associations of PRU with MACE in a stable population.

4.2. VerifyNow® cutoff value To date, very few studies have examined the association between platelet reactivity and MACE in prasugrel-treated patients, or identified possible cutoff values for platelet reactivity as a predictor of MACE. In this study, we focused on the fact that the risk of adverse events, including occlusive and bleeding events, is greatest in the acute phase after PCI and decreases thereafter in ACS patients treated with either drug. In PRASFIT-ACS, most of the MACEs occurred within 3 days of PCI. Therefore, we examined the association between platelet activity and the incidence of MACE in the acute period after the LD in this post-hoc analysis. We have demonstrated that the PRU at 5–12 h after the LD of ADP receptor antagonists is a clinically meaningful parameter in terms of the risk and benefits of antiplatelet drugs in Japanese ACS patients.

Fig. 4. Cumulative incidence of major adverse cardiovascular events from baseline through to 24 weeks according to platelet reactivity units ≤262 or N262 at 5–12 h after the loading dose. The inset shows the cumulative incidence from baseline through to day 3. CI: confidence interval; MACE: major adverse cardiovascular events; OR: odds ratio; PRU: platelet reactivity unit.

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Fig. 5. Proportions of patients with platelet reactivity units N262. PRU: platelet reactivity unit.

The optimal PRU cutoff value was ≤262 at 5–12 h after the LD in the present study. These findings are supported by the results of multivariate Cox regression analysis and indicate that PRU should be maintained at 262 to prevent MACE within 3 days after PCI. Because prasugrel at a LD/ MD of 20 mg/3.75 mg achieved a significantly higher response rate in terms of PRU ≤262 than standard doses of clopidogrel and was associated with a lower incidence of MACE, this adjusted-dose prasugrel regimen should achieve a lower incidence of ischemic events in Japanese patients undergoing planned PCI for ACS. In prior studies involving Western patients, the optimal PRU cutoff values were 240 [15,22], 235 [23], and 208 [10,16]. In our study of Japanese patients, the optimal cutoff value was 262. In Korean patients with/without acute myocardial infarction undergoing PCI, the prevalence of ischemic events over 1 year was significantly higher in patients with a PRU ≥272 at 12–24 h after PCI than in patients with a PRU b272 [24]. For example, the mean PRU at baseline in patients with ACS in the TRILOGY (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) sub-study [25] was between 200 and 250 in patients aged b 75 years and weighing ≥60 kg, although 95% of patients in that study received clopidogrel before randomization, which probably reduced the PRU value at the baseline measurement. In the GRAVITAS study [16], the median PRU was about 282 among patients with high on-treatment residual platelet reactivity and 151 in patients with low on-treatment platelet reactivity, but most patients received clopidogrel before randomization to the study drug. In the present study, the mean PRU at baseline was 324.5 ± 59.0 and 325.3 ± 64.4 in the prasugrel and clopidogrel groups, respectively. Considering these findings, it is possible that greater reductions in PRU from baseline, rather than achieving a target PRU, may be associated with a reduced risk of MACE. These differences in values also highlight the difficulty of directly comparing cutoff values and baseline PRU values among studies because of differences in study characteristics, including the time at which PRU was measured, treatment with an antiplatelet drug before the ‘baseline’ PRU measurement, duration of follow-up, and the clinical settings/patients. In fact, in one study that performed a bootstrap analysis of 10,000 replicates, the predicted cutoff was 235 and the 95% CI was 174–291 PRU [23]. Likewise, in a collaborative meta-analysis of six studies, the optimal cutoff for a composite of death, MI, or stent thrombosis was 230 [26]. Thus, differences in cutoff values among studies may be entirely reasonable owing to study features, or there may be clinical implications for the results. Another factor that should be considered is the difference in PRU measured before starting treatment. 4.3. CYP2C19 phenotype Clopidogrel may not achieve optimal inhibition of platelet reactivity in some patients, a phenomenon that is largely attributed to the presence of reduced-function CYP2C19 alleles [6,27,28]. In the present

study, the LD of clopidogrel did not reduce PRU for up to 12 h and the proportion of patients in the clopidogrel group with PRU ≤ 262 was smaller among patients with reduced-function alleles than among patients with normal function alleles. By contrast, the efficacy of prasugrel was hardly affected by reduced-function CYP2C19 alleles, and these favorable properties of prasugrel can be attributed to its rapid and potent P2Y12 inhibitory effects.

4.4. Limitations We need to mention several important limitations. First, this was a post-hoc analysis that was performed to investigate the relationship between platelet-reactivity and MACE. Therefore, a large prospective study is needed to confirm the clinical relevance of the PRU cutoff value determined here. Second, the ACS patients included in this study may not represent the types of patients treated in real-world settings. Thus, the utility of PRU may be not identical in clinical practice. The LD and MD of prasugrel used in the present study were about 1/3 of the doses approved in Western countries. Therefore, it may be difficult to translate the present results to clinical practice in Western countries. Nevertheless, clopidogrel was used at standard doses. It is also notable that the HR for the incidence of MACE was similar to that in each region of TRITON-TIMI 38 [11]. Thus, we believe that PRU ≤262 is a clinically relevant cutoff value for preventing MACE during the acute phase after PCI in Japanese patients. We must also consider that the predictive value of the obtained cutoff value might be low because of the relatively small area under the curve (0.58). Finally, some genetic analyses have shown that CYP2C19 polymorphisms are more frequent in Asian populations than in Western populations [29]. Thus, we cannot exclude the possibility that ethnic factors may contribute to the differences in the PRU cutoff values. Accordingly, further studies should assess the possible effects of ethnicity on PRU cutoff values.

Table 3 Results of Cox multivariable regression analysis. Variable

Adjusted HR

95% CI

p value

PRU (N262 vs. ≤262) Treatment with clopidogrel (vs. prasugrel) Multivessel disease (vs. no) Hypertension Dyslipidemia Current smoker (vs. no) Prior MI (yes vs. no)

2.02 1.10 1.97 1.33 1.36 0.85 1.96

1.05–3.90 0.57–2.12 1.13–3.43 0.66–2.66 0.66–2.80 0.49–1.54 0.77–4.96

b0.05 0.77 b0.05 0.43 0.41 0.58 0.16

HR: hazard ratio; CI: confidence interval; PRU: platelet reactivity unit; MI: myocardial infarction.


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Fig. 6. Proportion of patients with platelet reactivity units ≤262 at 5–12 h after the loading dose. The significance of differences was tested using the χ2 test. PRU: platelet reactivity unit.

5. Conclusions We found that PRU ≤262 at 5–12 h after the LD was a clinically relevant cutoff value for preventing MACE during the acute, periprocedural period (up to 3 days) after PCI. The proportion of non-responders (i.e., PRU N 262) was significantly lower in the prasugrel group with a dose adjusted for Japanese ACS patients (LD/MD: 20 mg/3.75 mg) than in the clopidogrel group treated with a standard dose (300 mg/ 75 mg). This difference was apparent in patients with normal or reduced-function CYP2C19 polymorphisms. Financial support This study was sponsored by Daiichi Sankyo Co., Ltd. (Tokyo, Japan). The sponsor contributed to the study design as well as the collection, analysis and interpretation of data. Daiichi Sankyo Co., Ltd. also funded publication support services and participated in the decision to submit this article for publication. However, all authors approved the final draft of the manuscript and independently decided to submit the article for publication. Conflict of interest Masato Nakamura has received research grants from Daiichi Sankyo Co., Ltd. and honoraria from AstraZeneca K.K., Daiichi Sankyo Co., Ltd, and Sanofi K.K. Takaaki Isshiki has received research grants from Daiichi

Sankyo Co., Ltd. and Sanofi K.K., and honoraria from AstraZeneca K.K., Daiichi Sankyo Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Sanofi K.K. Takeshi Kimura has received research grants from Daiichi Sankyo Co., Ltd. and Sanofi K.K. Hisao Ogawa has received research grants and honoraria from Astellas Pharma Inc., AstraZeneca K.K., Bayer Yakuhin, Boehringer Ingelheim Japan, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd, Dainippon Sumitomo Pharma Co., Ltd., Eisai Co., Ltd., Kowa Company Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Shionogi & Co., Ltd., and Takeda Pharmaceutical Co., Ltd., and honoraria from Kyowa Hakko Kirin Co., Ltd., and Mochida. Hiroyoshi Yokoi has received research grants and honoraria from Daiichi Sankyo Co., Ltd. Shinsuke Nanto has received research grants from Abbot Vascular Japan, Boston Scientific Japan, Daiichi Sankyo Co., Ltd., Medtronic, Sanofi K.K., St. Jude Medical Japan, and Terumo, and honoraria from Daiichi Sankyo Co., Ltd., Medtronic, Otsuka Pharmaceutical Co., Ltd., Sanofi K.K., and Takeda Pharmaceutical Co., Ltd. Morimasa Takayama has received research grants from Daiichi Sankyo Co., Ltd., and honoraria from Abbot Vascular Japan, Daiichi Sankyo Co., Ltd., and Kaneka Medics Co., Ltd. Kazuo Kitagawa has received research grants from Boehringer Ingelheim Japan and Sanofi K.K., and honoraria from Daiichi Sankyo Co., Ltd. and Sanofi K.K. Yasuo Ikeda has received honoraria from Daiichi Sankyo Co., Ltd., and research grants from Daiichi Sankyo Co., Ltd. and Sanofi K.K. Shigeru Saito has received research grants from Daiichi Sankyo Co., Ltd., and honoraria from Abbot Vascular Japan, Boston Scientific Japan., Daiichi Sankyo Co., Ltd., and Medtronic.

Fig. 7. Effects of normal function or reduced-function CYP2C19 alleles on platelet reactivity. (A) Patients with reduced-function CYP2C19 alleles. (B) Patients with normal-function CYP2C19 alleles. *p b 0.0001 vs. clopidogrel-treated patients by repeated measures ANOVA; the least square mean in the model was compared among groups at each time point, and time points showing a significant difference are marked with an asterisk. PCI: percutaneous coronary intervention; PRU: platelet reactivity unit.

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Authors' contributions Masato Nakamura, Shigeru Saito, Takaaki Isshiki, Takeshi Kimura, Hisao Ogawa and Hiroyoshi Yokoi contributed to the study design, conduct, and/or data collection; Shinsuke Nanto, Morimasa Takayama, and Kazuo Kitagawa contributed to the analysis and interpretation of efficacy data; Yasuo Ikeda analyzed and interpreted platelet reactivity data; Masato Nakamura and Shigeru Saito wrote and reviewed the manuscript; all of the authors approved the final draft of the manuscript. Acknowledgments This study was sponsored by Daiichi Sankyo Co., Ltd. (Tokyo, Japan). The authors thank all investigators and research staff for their help. We also wish to acknowledge the contributions of the following members of the Independent Data Monitoring Committee: Hideki Origasa, PhD (Toyama University), Kazuhiro Sase, MD (Juntendo University), Kazuo Umemura, MD (Hamamatsu University), and Takanari Kitazono, MD (Kyushu University). We thank SOC Co Ltd, Tokyo, Japan, for providing the SAS software used in the data analysis. We would also like to thank Dr Nicholas Smith, PhD, for providing medical writing services during the preparation of this manuscript. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2015.01.026. References [1] J.L. Anderson, R.S. Wright, C.D. Adams, et al., 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, J. Am. Coll. Cardiol. 60 (2012) 645–681. [2] F.G. Kushner, M. Hand, S.C. Smith Jr., et al., 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines, Circulation 120 (2009) 2271–2306. [3] M. Cattaneo, New P2Y12 inhibitors, Circulation 121 (2010) 171–179. [4] J.T. Brandt, S.L. Close, S.J. Iturria, et al., Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel, J. Thromb. Haemost. 5 (2007) 2429–2436. [5] J.S. Hulot, A. Bura, E. Villard, et al., Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects, Blood 108 (2006) 2244–2247. [6] J.L. Mega, S.L. Close, S.D. Wiviott, et al., Cytochrome P-450 polymorphisms and response to clopidogrel, N. Engl. J. Med. 360 (2009) 354–362. [7] L. Bonello, U.S. Tantry, R. Marcucci, et al., Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate, J. Am. Coll. Cardiol. 56 (2010) 919–933. [8] F. Mangiacapra, G. Patti, E. Barbato, et al., A therapeutic window for platelet reactivity for patients undergoing elective percutaneous coronary intervention: results of the ARMYDA-PROVE (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity for Outcome Validation Effort) study, JACC Cardiovasc. Interv. 5 (2012) 281–289.

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