Author + information
- Received June 4, 2012
- Revision received July 10, 2012
- Accepted July 19, 2012
- Published online December 1, 2012.
- Thomas Cuisset, MD, PhD⁎,†,‡,⁎ (, )
- Marie Loosveld, MD†,‡,§,
- Pierre Emmanuel Morange, MD, PhD†,‡,§,
- Jacques Quilici, MD⁎,†,
- Pierre Julien Moro, MD⁎,‡,
- Noémie Saut, PhD†,‡,
- Bénédicte Gaborit, MD†,‡,
- Christel Castelli, PhD∥,
- Shirley Beguin, PhD¶,
- Charlotte Grosdidier, MD†,‡,§,
- Laurent Fourcade, MD#,
- Jean-Louis Bonnet, MD⁎,†,‡ and
- Marie-Christine Alessi, MD, PhD†,‡,§
- ↵⁎Reprint requests and correspondence:
Dr. Thomas Cuisset, Aix-Marseille Université, Faculté de Médecine, Dèpartement de Cardiologie, CHU Timone, 264 rue Saint Pierre, F-13385 Marseille, France
Objectives The present study was designed to assess the effect of genetic variants on chronic biological response to prasugrel and bleeding complications.
Background CYP2C19*2 loss-of-function allele and CYP2C19*17 gain-of-function allele have been linked with response to clopidogrel, but preliminary data did not show any significant influence of these alleles on prasugrel effect.
Methods A total of 213 patients undergoing successful coronary stenting for acute coronary syndrome and discharged with prasugrel 10 mg daily were included. Prasugrel response was assessed at 1 month with the platelet reactivity index (PRI) vasodilator-stimulated phosphoprotein (VASP) and high on-treatment platelet reactivity (HTPR) defined as PRI VASP > 50% and hyper-response as PRI VASP <75th percentile (PRI VASP < 17%). CYP2C19*2 and CYP2C19*17 genotyping were performed.
Results Carriers of loss-of-function *2 allele had significantly higher PRI VASP than noncarriers (33 ± 15% vs. 27 ± 14%, p = 0.03) and higher rate of HTPR (16% vs. 4%, p = 0.01). Conversely, carriers of *17 gain-of-function allele had significantly lower PRI VASP than noncarriers (25 ± 13% vs. 31 ± 15%, p = 0.03, p = 0.03), lower rate of HTPR (1% vs. 10%, p = 0.02), higher rate of hyper-response (34% vs. 21%, p = 0.02), and higher rate of bleeding complications than noncarriers: 23% versus 11%, (odds ratio [95% confidence interval]: 2.5 [1.2 to 5.4]; p = 0.02). No significant influence of genotypes on platelet reactivity assessed by adenosine diphosphate–induced platelet aggregation was observed.
Conclusions The present study shows a significant influence of CYP2C19*2 and *17 alleles on response to chronic treatment by prasugrel 10 mg daily and occurrence of bleeding complications.
Dual antiplatelet therapy with aspirin and clopidogrel has been the gold standard therapy for patients undergoing percutaneous coronary interventions (PCI) and/or after acute coronary syndrome (ACS) (1–3). The large variability of the clopidogrel response has been described with clinical consequences (4). After intestinal absorption, clopidogrel biotransformation into its active metabolite is mainly mediated by hepatic cytochrome P450 (CYP). Recent data showed that the CYP2C19*2 loss-of-function allele is associated with a marked decrease in platelet response to clopidogrel in unstable patients (5) and an impaired prognosis in clopidogrel-treated patients (6,7). By contrast, the gain-of-function allele CYP2C19*17 has been linked with a better response to clopidogrel (8) and, accordingly, a higher risk of bleeding (9). Recently, a third-generation thienopyridine, prasugrel, has provided faster, more potent and predictable platelet inhibition compared with clopidogrel (10,11). This higher degree of platelet inhibition resulting in a significant reduction of ischemic events was associated with an increase of bleeding complications in the overall TRITON TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction) study (12). Like clopidogrel, it is a prodrug that irreversibly blocks the P2Y12 platelet receptor after hepatic transformation and could be affected by CYP450 genetic variants. However, previous studies did not find any significant influence of CYP genetic variants on pharmacokinetic and pharmacodynamic response to prasugrel and on clinical outcome in prasugrel-treated patients (13,14), although a trend was observed in the Mega et al. study (13). These studies included both ACS patients and healthy subjects, assessed response to 60-mg loading dose, and used light transmittance aggregometry (LTA) as the platelet test, though the influence of such genetic variants on response to maintenance therapy in ACS patients using the most specific test of P2Y12 inhibition, the platelet reactivity index (PRI) vasodilator-stimulated phosphoprotein (VASP), remained unknown. We therefore designed the present study to assess the influence of CYP2C19*2 and *17 alleles on prasugrel response and bleeding complications in patients treated with prasugrel 10 mg daily after PCI for ACS.
Consecutive patients admitted for non–ST-segment elevation ACS or ST-segment elevation myocardial infarction in our institution were eligible for this prospective study if they had undergone successful PCI and were treated at discharge with prasugrel 10 mg. The exclusion criteria were a history of bleeding diathesis, prior stroke or transient ischemic attack, contraindications to antiplatelet therapy, platelet count <100 × 109/l, and creatinine clearance <25 ml/min. Patients received loading doses of aspirin 250 mg and prasugrel 60 mg and, as discharge therapy, oral doses of 75-mg aspirin and 10- mg prasugrel daily. Prasugrel response was assessed at 1-month clinical follow-up by PRI VASP. Adherence was systematically assessed during this consultation. The study protocol was approved by the ethics committee of our institution, and patients gave written informed consent for participation.
Blood samples for testing clopidogrel response were drawn at 1-month follow-up. For patients who experienced significant bleeding (Bleeding Academic Research Consortium [BARC] ≥2) and who needed to stop prasugrel, platelet testing was performed in our center before discontinuation. Blood was sent immediately to the hemostasis laboratory to determine the VASP phosphorylation state of whole blood. We used a standardized flow cytometric assay (Platelet VASP; Diagnostica Stago/Biocytex, Asnières, France), which is an adaptation of the method of Schwarz et al. (15) previously described. PRI VASP was calculated from the median fluorescence intensity (MFI) of samples incubated with prostaglandin E1 (PGE1) or PGE1 and adenosine diphosphate (ADP) according to the formula: PRI VASP = [(MFI(PGE1) − MFI(PGE1+ADP)/MFIPGE1] × 100. High on-treatment platelet reactivity (HTPR) was defined as PRI VASP >50% as recently proposed (16), and hyper-response as PRI VASP below the 75th percentile by quartile repartition. Blood was immediately collected in an evacuated blood sample tube containing 3.8% trisodium citrate and filled to capacity. The blood–citrate mixture was centrifuged at 120 g for 5 min. The resulting platelet-rich plasma was kept at room temperature for use within 1 h. The platelet count was determined in the platelet-rich plasma sample and adjusted to 2.5 × 108 ml−1 with homologous platelet-poor plasma. Platelets were stimulated with ADP (10 μmol/l) and aggregation was assessed with a PAP4 Aggregometer (Biodata Corporation, Wellcome, Paris, France). Aggregation was expressed as the percentage change in light transmittance from baseline, with platelet-poor plasma as reference. Here, we report data on the maximal intensity of ADP-induced platelet aggregation (ADP-Ag). The coefficient of variation of maximal intensity of platelet aggregation with ADP was measured at 6.5%.
Genomic DNA was extracted from peripheral blood leukocytes by the salting-out method. CYP2C19*2 and CYP2C19*17 genotyping was done using amplification refractory mutation system PCR in duplex reaction. Primers (Invitrogen, Carlsbad, California) are as follows: *2 forward: cag agc ttg gca tat tgt atc, *2 reverse: tat cgc aag cag tca cat aac; *2 G specific (sense): act atc att gat tat ttc ccg and *2 A specific (antisense): gta att tgt tat ggg ttc ct; *17 forward: aag aag cct tag ttt ctc aag, *17 reverse: aaacacctttaccatttaaccc; *17 T specific (sense): tgt ctt ctg ttc tca aag ta and *17 C specific (antisense): atta tct ctt aca tca gag atg. Size of the PCR products generated: CYP2C19*2 forward/reverse: 373 bp, *2 allele G (normal): 283 bp, and *2 allele A (mutated): 129 bp; CYP2C19*17 forward/reverse: 507 bp, *17 allele C (normal): 330 bp, and *17 allele T (mutated): 218 bp. Reactions were made in a final volume of 12.5 μl, using 200 nmol/l of primer except for *2 A primer (300 nmol/l), 0.15 unit of Taq DNA polymerase (Qbiotaq, MP Biomedicals, Solon, Ohio) in its accompanying buffer, 200 μm of accompanying deoxyribonucleotide triphosphates, and 25 ng of genomic DNA. Cycling conditions: first denaturing step: 90 min at 94°C, then 35 cycles of 30 min at 95°C, 30 min at 60°C, and 50 min at 72°C, final extension step: 3 h at 72°C and then cooling to 15°C. PCR products were run on 2% agarose gels, and genotypes were assigned according to the PCR products sizes observed. CYP2C19*2 and *17 are defined by rs4244285 and rs12248560, respectively. Hardy-Weinberg equilibrium was tested for each polymorphism to detect potential stratification bias or genotyping errors.
Clinical follow-up was planned for all patients at 1 month. The clinical endpoint was the occurrence of bleeding events according to the BARC consensus definitions with Type 1 and 2 or 3 or 5 (Type 4 was not expected because no patient had planned coronary artery bypass grafting) (17). Bleeding complications according to the Thrombolysis In Myocardial Infarction (TIMI) definition were also collected (12). Ischemic events were also collected using the combined endpoint of cardiovascular death, myocardial infarction, definite or probable stent thrombosis, and stroke. Definite or probable stent thrombosis was defined as the definite occurrence of a thrombotic event, according to the Academic Research Consortium classification (18). To be considered a primary endpoint event, a myocardial infarction must be distinct from the index event and defined with the universal definition of myocardial infarction (19). Stroke was defined as a rapid onset of a new persistent, neurological deficit that lasts for more than 24 h.
The primary endpoint of the present study was the effect of CYP2C19*2 and *17 allele on prasugrel response assessed by PRI VASP, incidence of HTPR defined as PRI VASP > 50%, and hyper-response defined as PRI VASP below the 75th percentile. Secondary endpoints assessed the bleeding complications and influence of both prasugrel response and genotypes on bleeding risk.
Statistical analysis was performed using the GraphPad Prism Software (v. 4.00, GraphPad Software, La Jolla, California). Continuous variables were analyzed for a normal distribution with the Shapiro-Wilk test and expressed as mean ± SD. Categorical variables are expressed as frequencies and percentages. Comparisons between groups were made with the chi-square or Fisher exact test for categorical variables and t test for continuous variables. One-way analysis of variance was used for comparison between different groups. Values of p < 0.05 were considered statistically significant. Assuming that carriers of *2 and *17 alleles represent one-third of the entire population, and expecting in these patients a 5% absolute difference in PRI VASP compared with patients who were noncarriers, a total of at least 205 patients were needed to detect the expected difference with an estimated power of 80% at a 2-sided alpha of 0.05.
A total of 213 patients undergoing successful PCI for ACS and discharged with prasugrel 10 mg daily were prospectively included. Characteristics of the studied population are included in Table 1. In the whole population, the rate of patients with HTPR was 7% (n = 15). The present study included 15 patients (7%) older than 75 years, and 13 patients (6%) with low body weight. Prasugrel response (PRI VASP) and platelet reactivity (ADP-Ag) were not statistically different in these subgroups of patients. Neither PRI VASP nor clinical bleeding events differed by smoking status, unlike published reports regarding clopidogrel. The genotype frequencies for each allele considered separately were consistent with Hardy-Weinberg predictions, and genetic distributions are reported in Table 2.
Effect of genotypes on prasugrel response (PRI VASP)
At 1 month, patient who were carriers of loss-of-function *2 allele had significantly higher PRI VASP than noncarriers (33 ± 15% vs. 27 ± 14%, p = 0.03, Fig. 1) and a higher rate of HTPR (16% vs. 4%, p = 0.01, Fig. 2A). Conversely, patients who were carriers of *17 gain-of-function allele had significantly lower PRI VASP than noncarriers (25 ± 13% vs. 31 ± 15%, p = 0.03, Fig. 1) and lower risk of HTPR (1% vs. 10%, p = 0.02, Fig. 2B). We defined hyper-response as PRI VASP below the 75th percentile of the population by quartile repartition, identifying a threshold of PRI VASP <17%. In the whole cohort, 55 patients (26%) were hyper-responders. Incidence of hyper-response was significantly higher among carriers of *17 gain-of-function allele than in noncarriers: 34% (n = 25 of 73) versus 21% (n = 30 of 140), p = 0.02 (Fig. 3).
Effect of genotypes on platelet reactivity (LTA with ADP-Ag)
At 1 month, patients who were carriers of loss-of-function *2 allele did not have significantly higher ADP-Ag values than noncarriers (48 ± 15% vs. 46 ± 14%, p = 0.78), and patients who were carriers of *17 gain-of-function allele did not have significantly lower ADP-Ag values than noncarriers (45 ± 13% vs. 48 ± 14%, p = 0.36).
Classification of patients according to genotypes: interaction of *2 and *17 alleles
Given the significant association between PRI VASP and genetic variants, patients were classified according to their genotypes as poor metabolizers (*2 loss-of-function allele carriers/*17 gain-of-function allele noncarriers) (n = 42), intermediate metabolizers (*2 loss-of-function allele carriers/*17 gain-of-function allele carriers or *2 loss-of-function allele noncarriers/*17 gain-of-function allele noncarriers) (n = 107), and ultrametabolizers (*2 loss-of-function allele noncarriers/*17 gain-of-function allele carriers) (n = 64).
This classification was associated with the mean PRI VASP values and with the incidence of HTPR on prasugrel 10 mg (Figs. 4A and 4B). Indeed, the rate of patients with HTPR was 19% in poor metabolizers (n = 8 of 42), 6% in intermediate metabolizers (n = 6 of 107), and 1% in ultrametabolizers (n = 1 of 64) (Fig. 4B) (p = 0.002). For the rate of hyper-response, we observed a trend with a numerically higher rate of hyper-response of 14% in poor metabolizers (n = 6 of 42), 24% in intermediate metabolizers (n = 26 of 107), and 36% in ultrametabolizers (n = 23 of 64) (p = 0.10).
In the overall population, the incidence of bleeding complications at 1 month was 15% (n = 32), including 16 BARC 1, 13 BARC 2, and 3 BARC 3 bleeding events. Patients who had bleeding complications according to BARC definitions had significantly lower PRI VASP than patients without complications: 24 ± 14% versus 30.1 ± 14% (p = 0.03) (Fig. 5). Patients with hyper-response had a significantly higher rate of bleeding complications compared with patients without hyper-response: 24% (n = 13 of 55) versus 12% (n = 19 of 158), odds ratio (OR) [95% confidence interval (CI)]: 2.2 [1 to 5]; p = 0.04) (Fig. 6). Values of ADP-Ag were not significantly different between patients with and without BARC bleeding complications (data not shown). For the impact of genetic variants on clinical outcomes; patients who were carriers of *17 gain-of-function allele had a significantly higher rate of BARC bleeding complications than noncarriers: 23% versus 11%, (OR [95% CI]: 2.5 [1.2 to 5.4]; p = 0.02) (Fig. 7). In the different groups according to genotypes, we observed a nonsignificant trend for the distribution of bleeding complications: 10% (n = 4) in poor metabolizers, 14% (n = 15) in intermediate metabolizers, and 20% (n = 13) in the ultrametabolizers group (p = 0.20).
During the 1-month follow-up, we observed only 2 ischemic events, including 1 definite and 1 probable stent thrombosis. Genetic and platelet parameters were not significantly different among patients with or without ischemic events (data not shown). Using the TIMI definition for bleeding complications, only 1 TIMI major bleeding and 7 TIMI minor bleeding occurred during the follow-up, without statistical significant association with genotypes or platelet testing.
In the present study, we observed a significant effect of CYP2C19*2 and *17 alleles on prasugrel response and bleeding events in patients treated with 10 mg daily after PCI for ACS. This study provides for the first time, to the best of our knowledge, data about CYP2C19 genetic polymorphisms' modulation of platelet response and bleeding risk in prasugrel-treated patients after ACS.
A large amount of data has demonstrated the influence of CYP2C19*2 loss-of-function allele on platelet response to clopidogrel in unstable patients (5) and an impaired prognosis in clopidogrel-treated patients (6,7). By contrast, the gain-of-function *17 allele was described as associated with a better response to clopidogrel (8) and higher risk of bleeding (9). Recently, a third-generation thienopyridine, prasugrel, provides a faster, more potent and predictable platelet inhibition compared with clopidogrel (10,11). This higher degree of platelet inhibition resulting in a significant reduction of ischemic events was associated with an increase of bleeding complications in the TRITON TIMI 38 study (12). Indeed, in the present study, we observed a more predictable degree of platelet inhibition with prasugrel with a low rate of patients with residual HTPR while treated with prasugrel. These results are not in line with those previously published by Bonello et al. (16) showing a significant proportion of patients with HTPR after the 60 mg loading dose. This discrepancy illustrates that a remaining critical issue of platelet testing is the timing and delay from loading dose to sampling for antiplatelet therapy monitoring. A possible explanation of the observed findings (16), is that the delay between loading dose and sampling was too short to allow appropriate effectiveness of the treatment. In a substudy of TRITON-TIMI 38, Michelson et al. (20) found that 24% patients had HTPR at 1 month on prasugrel 10 mg daily. This discrepancy could be explained by the patient characteristics, with higher body mass index and incidence of diabetes in the Michelson's study (20). Recently, results from several studies performed were in line with our results, with a low rate (<10%) of patients with HTPR while treated with prasugrel 10 mg daily (21–23). However, in the present study, we still observed variability of response to prasugrel, which could be explained by the relatively high incidence of factors known to influence thienopyridine metabolism, including prasugrel, such as acute myocardial infarction, diabetes, and patients with a high body mass index.
Like clopidogrel, prasugrel is a prodrug that irreversibly blocks the P2Y12 platelet receptor after hepatic transformation and could be affected by CYP450 genetic variants. Previous studies found a significant influence of CYP genetic variants on pharmacokinetic and pharmacodynamic response to clopidogrel, but not to prasugrel (13,14), although a trend was observed in the Mega et al. study (13), suggesting that the absence of difference might be due to a lack of power in 238 healthy volunteers (13,14). However, these studies included mainly healthy subjects, assessed biological response to 60-mg prasugrel loading dose, and used LTA as platelet test. Moreover, the CYP2C19*17 allele was not included in the genetic subanalysis of the TRITON study (13). Our present results are in line with those previously published studies (13,14) observing no significant association between on-prasugrel platelet reactivity assessed by ADP-Ag and these genetic variants. However, we originally observed a significant effect of CYP2C19 genotypes on prasugrel response assessed by PRI VASP. Among each genotype, we still observed a large variability of platelet response to prasugrel. This finding highlights the fact that prasugrel response, as described for clopidogrel response, is a multifactorial process and that genetic modulation is only, although strong, 1 factor explaining variability of response (24). We thus observed in our study a clear discordance between the effect of genetic variants on platelet reactivity (ADP-Ag) and prasugrel response (PRI VASP). For years, several platelet tests have been proposed to assess response to thienopyridine. In clopidogrel-treated patients, different tests have significant correlation but their agreement to identify specific patients as responders or not are rather low (25). Accordingly, the gold standard test to assess response to thienopyridine is still controversial, and the best option to predict clinical outcomes between a specific pharmacological test (PRI VASP) and more “global” assessment of platelet reactivity (LTA, VerifyNow) is still unclear. In the important POPULAR (Do Point-of-Care Platelet Function Assays Predict Clinical Outcomes in Clopidogrel Pre-Treated Patients Undergoing Elective PCI) study (26), various platelet tests were tested to assess clinical outcomes. Only some of the tests used were able to predict ischemic events, suggesting different performances of platelet tests to predict clinical outcome. Our results, focusing on prasugrel-treated patients, are in line with this study; only PRI VASP was significantly associated with bleeding events, suggesting PRI VASP as the best option for bleeding risk prediction with prasugrel. Indeed, it is interesting to note that ADP-Ag is scarcely lower than 20%, in contrast to PRI-VASP, which may reach 0%, indicating a limit of ADP-Ag to detect strong degree of P2Y12 inhibition, suggesting PRI VASP as the best option in patients treated with strong P2Y12 inhibitors to assess platelet response and bleeding risk. Accordingly, although ADP-Ag has a greater amount of evidence for a relationship with ischemic events (4), PRI VASP might be a better test to assess bleeding risk with new P2Y12 blockers providing a strong degree of P2Y12 pathway inhibition. In the present study, we also introduced the notion of hyper-response to prasugrel, incorporating a new concept with a threshold value for PRI VASP and identifying hyper-responder patients with high bleeding risk with new P2Y12 blockers. Together with HTPR defined with clopidogrel as PRI VASP >50% (16), this might suggest an optimal therapeutic window (17% to 50%) for patients treated with P2Y12 inhibitors.
Also, results on LTA might have been due to the amount of ADP used (10 μmol/l), which is an intermediate dose of ADP to stimulate platelets highly inhibited by a P2Y12 antagonist. The 20 μmol/l dose might be more appropriate as shown in the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) study with clopidogrel (27). In addition, for prasugrel metabolism, in vitro studies indicate the active prasugrel metabolite generation occurs primarily by CYP3A and CYP2B6 with lesser contributions by CYP2C9 and CYP2C19 (28). However, our present results suggest that CYP2C19 participates in active metabolite formation.
Clinical relevance of such findings will have to be addressed in further clinical trials, including high-risk patients and all genetic variants thought to influence clinical prognosis. Indeed, the potential effect of CYP2C19*17 on bleeding risk in prasugrel-treated patients could be of great clinical interest, aiming to provide genetic-based individualized therapy. In the present study, we included BARC 1 bleedings in the analysis. These bleedings might not be clinically meaningful by themselves and could be considered as minimal or nuisance bleedings. However, these events might lead to premature discontinuation of the drug in daily practice as shown in clopidogrel- and prasugrel-treated patients (29,30). Also, this study emphasizes the fact that platelet function test and genotyping may be complementary to assess both ischemic and bleeding risk. It also shows that genetics are important when using a thienopyridine, either clopidogrel or prasugrel, and that risk scoring with genetic information might be useful also for bleeding risk as shown for stent thrombosis in the recently published paper by Cayla et al. (31). Accordingly, genetically tailored therapy could be tested with switching poor metabolizers to prasugrel and fast metabolizers to clopidogrel. However, the clinical benefit of such a strategy should be tested in further randomized clinical trials, whereas data on a switch are only available from biological studies (32,33).
The main limitation of the present study is its limited sample size and the lack of power to detect an effect on endpoint, such as mortality or stent thrombosis. Also, effect on bleeding was observed with inclusion of minimal BARC 1 bleedings. Finally, assessment of response to chronic antiplatelet therapy may have been modified by lack of compliance. However, in the present study, efforts were made to improve compliance and to detect noncompliant patients.
The authors thank the nurses' team and technicians in executing this study, and the hematology laboratory, Conception Hospital for VASP analysis.
Dr. Cuisset has received consultant fees from Daiichi-Sankyo and Eli Lilly, and lecture fees from AstraZeneca, Abbott Vascular, Biotronik, Boston Scientific, Cordis, Daiichi-Sankyo, Edwards, Eli Lilly, Sanofi-Aventis, and Servier. Dr. Alessi has been a regional board member of Eli Lilly and received research funding from Sanofi-Aventis. The other authors have stated that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute coronary syndrome
- adenosine diphosphate
- adenosine diphosphate–induced platelet aggregation
- Bleeding Academic Research Consortium
- confidence interval
- cytochrome P450
- high on-treatment platelet reactivity
- light transmittance aggregometry
- odds ratio
- median fluorescence intensity
- percutaneous coronary interventions
- polymerase chain reaction
- prostaglandin E1
- platelet reactivity index
- Thrombolysis In Myocardial Infarction
- vasodilator-stimulated phosphoprotein
- Received June 4, 2012.
- Revision received July 10, 2012.
- Accepted July 19, 2012.
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