Genetic testing in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a cost‐effectiveness analysis

Summary. Background: The CYP2C19 genotype is a predictor of adverse cardiovascular events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) treated with clopidogrel. Objectives: We aimed to evaluate the cost‐effectiveness of a CYP2C19*2 genotype‐guided strategy of antiplatelet therapy in ACS patients undergoing PCI, compared with two ‘no testing’ strategies (empiric clopidogrel or prasugrel). Methods: We developed a Markov model to compare three strategies. The model captured adverse cardiovascular events and antiplatelet‐related complications. Costs were expressed in 2010 US dollars and estimated using diagnosis‐related group codes and Medicare reimbursement rates. The net wholesale price for prasugrel was estimated as $5.45 per day. A generic estimate for clopidogrel of $1.00 per day was used and genetic testing was assumed to cost $500. Results: Base case analyses demonstrated little difference between treatment strategies. The genetic testing‐guided strategy yielded the most QALYs and was the least costly. Over 15 months, total costs were $18 lower with a gain of 0.004 QALY in the genotype‐guided strategy compared with empiric clopidogrel, and $899 lower with a gain of 0.0005 QALY compared with empiric prasugrel. The strongest predictor of the preferred strategy was the relative risk of thrombotic events in carriers compared with wild‐type individuals treated with clopidogrel. Above a 47% increased risk, a genotype‐guided strategy was the dominant strategy. Above a clopidogrel cost of $3.96 per day, genetic testing was no longer dominant but remained cost‐effective. Conclusions: Among ACS patients undergoing PCI, a genotype‐guided strategy yields similar outcomes to empiric approaches to treatment, but is marginally less costly and more effective.     

Personalizing antiplatelet prescribing using genetics for patients undergoing percutaneous coronary intervention

Introduction. Clopidogrel is commonly prescribed with aspirin to reduce the risk for adverse cardiovascular events after percutaneous coronary intervention (PCI). However, there is significant inter-patient variability in clopidogrel response. The CYP2C19 enzyme is involved in the biotransformation of clopidogrel to its pharmacologically active form, and variation in the CYP2C19 gene contributes to clopidogrel response variability.

Areas covered. This article describes the impact of CYP2C19 genotype on clopidogrel pharmacokinetics, pharmacodynamics, and effectiveness. Examples of clinical implementation of CYP2C19 genotype-guided antiplatelet therapy for patients undergoing PCI are also described as are emerging outcomes data with this treatment approach.

Expert commentary. A large clinical trial evaluating outcomes with CYP2C19 genotype-guided antiplatelet therapy after PCI is on-going. In the meantime, data from pragmatic and observational studies and smaller trials support improved outcomes with genotyping after PCI and use of alternative antiplatelet therapy in patients with a CYP2C19 genotype associated with reduced clopidogrel effectiveness.     

Antiplatelet effects of prasugrel vs. double clopidogrel in patients on hemodialysis and with high on‐treatment platelet reactivity

Summary. Background: High on‐treatment platelet reactivity (HTPR) is frequent in patients on hemodialysis (HD) receiving clopidrogel. Objectives: The primary aim of this study was to determine the antiplatelet effects of prasugrel vs. high‐dose clopidogrel in patients on HD with HTPR. Patients/Methods: We performed a prospective, single‐center, single‐blind, investigator‐initiated, randomized, crossover study to compare platelet inhibition by prasugrel 10 mg day^?1 with that by high‐dose 150 mg day^?1 clopidogrel in 21 patients on chronic HD with HTPR. Platelet function was assessed with the VerifyNow assay, and genotyping was performed for CYP2C19*2 carriage. Results: The primary endpoint of platelet reactivity (PR, measured in P2Y12 reaction units [PRU]) was lower in patients receiving prasugrel (least squares [LS] estimate 156.6, 95% confidence interval [CI] 132.2–181.1) than in those receiving high‐dose clopidogrel (LS 279.9, 95% CI 255.4–304.3), P < 0.001). The LS mean differences between the two treatments were ? 113.4 PRU (95% CI ? 152.9 to ? 73.8, P < 0.001) and ? 163.8 PRU (95% CI ? 218.1 to ? 109.2, P < 0.001) in non‐carriers and carriers of at least one CYP2C19*2 allele, respectively. HTPR rates were lower for prasugrel than clopidogrel, in all patients (19% vs. 85.7%, P < 0.001) and in non‐carriers (25.7% vs. 80%, P = 0.003). All carriers continued to show HTPR while receiving high‐dose clopidogrel, but none showed it while receiving prasugrel. Conclusions: In HD patients exhibiting HTPR following standard clopidogrel treatment, prasugrel 10 mg day^–1 is significantly more efficient than doubling the clopidogrel dosage in achieving adequate platelet inhibition. Neither effect seems to be influenced by carriage of the loss‐of‐function CYP2C19*2 allele.     

A risk-benefit assessment of prasugrel, clopidogrel, and genotype-guided therapy in patients undergoing percutaneous coronary intervention

The objective of this study was to quantitatively evaluate the clinical benefits and harms of prasugrel, clopidogrel, and a CYP2C19 genotype-guided drug selection strategy for patients with acute coronary syndrome (ACS) and planned percutaneous coronary intervention (PCI). We used decision-analytic techniques to model the risks and benefits of alternative antiplatelet strategies. Sensitivity and scenario analyses were conducted to assess the uncertainty of the results. Prasugrel demonstrated little difference in net benefit as compared with clopidogrel (+0.02 quality-adjusted life-years (QALYs); 95% confidence range (CR), -0.23 to 0.21). The genotype-guided strategy had a 93% probability of greater net benefit as compared with clopidogrel (+0.05 QALYs; 95% CR, -0.02 to 0.11), and 66% probability of greater net benefit as compared with prasugrel (+0.03 QALYs; 95% CR, -0.13 to 0.24). Prasugrel and clopidogrel differ in their risk-benefit profiles but appear to offer similar net benefit on average. Use of patient-specific factors such as CYP2C19 genotype offers promise for developing a personalized medicine approach to antiplatelet treatment regimens.     

Antiplatelets in acute coronary syndrome: personal perspectives

High platelet reactivity (HPR) during dual-antiplatelet therapy is a marker of vascular risk, in particular stent thrombosis, in patients with acute coronary syndromes. Genetic determinants (CYP2C19*2 polymorphism), advanced age, female gender, diabetes and reduced ventricular function are related to a higher risk to develop HPR. In addition, inflammation and increased platelet turnover, as revealed by the elevated percentage of reticulate platelets in patients’ blood, that characterize the acute phase of acute coronary syndrome are associated with HPR. To overcome the limitation of clopidogrel, new antiplatelet agents (prasugrel and ticagrelor) were developed and the demonstration of their superiority over clopidogrel was obtained in the two randomized trials, TRITON TIMI 38 and PLATO. Due to the current possibility not a choice between multiple antiplatelet strategies, the future prospect is to include, in addition to clinical data and classical risk factors, the definition of platelet function during treatment in order to set a tailored therapy.     

CYP2C19 and ABCB1 genetic polymorphisms correlate with the recurrence of ischemic cardiovascular adverse events after clopidogrel treatment

Background

This study was aimed to investigate the correlation between CYP2C19 and ABCB1 polymorphisms and the recurrence of ischemic cardiovascular adverse events in patients with coronary artery disease treated with clopidogrel.

Methods

A total of 168 patients with coronary heart disease who underwent PCI operation and received clopidogrel treatment were enrolled. Dual antiplatelet therapy was applied to the treatment of patients for 2 years. Thromboelastography was used to test the efficiency of blood coagulation. Polymerase chain reaction (PCR) was used to detect CYP2C19 and ABCB1 3435CT polymorphisms. One‐year follow‐up visit was carried out to record the incidence of cardiovascular adverse events after drug‐eluting stent implantation was inset.

Results

Follow‐up visit results suggested that the patients with high on‐treatment platelet reactivity (HPR) had a higher recurrence rate of cardiovascular adverse events after PCI operation and clopidogrel treatment. Gene polymorphism testing results indicated that patients with CYP2C19*3 had a significantly higher incidence of HPR, whereas CYP2C19*2 and ABCB1 3435CT were not significantly correlated with HPR. Multivariable logistic regression analysis showed that CYP2C19*3 might be an independent predictive factor of post‐PCI HPR. In addition, CYP2C19*3 as well as post‐PCI HPR could function as independent predictive factors of cardiovascular adverse events.

Conclusion

CYP2C19*3 polymorphism could be an important predictive factor of HPR and ischemic cardiovascular adverse events after clopidogrel treatment.

     

Influence of high‐density lipoprotein and paraoxonase‐1 on platelet reactivity in patients with acute coronary syndromes receiving clopidogrel therapy

Summary. Background: The paraoxonase activity of the enzyme paraoxonase‐1 (PON‐1) associated with high‐density lipoprotein (HDL) may significantly influence clopidogrel’s antiplatelet and clinical efficacy as a result of its involvement in the clopidogrel biotransformation to the pharmacologically active thiol metabolite. We evaluated the possible relationships of HDL levels as well as PON‐1 activities and the Q192R genotype with clopidogrel’s antiplatelet efficacy in acute coronary syndrome (ACS) patients. Methods and results: The platelet aggregation, P‐selectin expression and platelet/leukocyte conjugates as well as the clopidogrel response variability (evaluated by the VASP phosphorylation test and expressed as platelet reactivity index, PRI) were assessed in 74 ACS patients undergoing percutaneous coronary intervention (PCI) in relation to the PON‐1 Q192R genotype and to serum HDL‐cholesterol levels, and PON‐1 (paraoxonase and arylesterase) activities. Patients were loaded with 600 mg of clopidogrel followed by 75 mg per day. HDL‐cholesterol levels and PON‐1 activities at baseline (before clopidogrel loading) were not altered at 5‐ and 30‐day post‐clopidogrel loading, whereas baseline platelet activation parameters were significantly attenuated. At 5 days, 17 patients were clopidogrel non‐responders (PRI: 64.2 ± 11.1%). HDL‐cholesterol was inversely associated with platelet activation parameters independently on platelet response variability to clopidogrel whereas a negative association between platelet activation parameters and paraoxonase activity was observed in patients adequately responding to clopidogrel but not in clopidogrel non‐responders. Similarly, the platelet activation markers were significantly higher in PON‐1 Q192Q genotype carriers compared with those having one or two R alleles only in patients adequately responding to clopidogrel. Conclusions: PON‐1 is an important determinant of clopidogrel antiplatelet efficacy only in patients adequately responding to clopidogrel. These findings may be clinically important in ACS patients receiving clopidogrel therapy, especially the first days after the episode.     

The gain‐of‐function variant allele CYP2C19*17: a double‐edged sword between thrombosis and bleeding in clopidogrel‐treated patients

Summary. Background: A large number of clinical studies have documented that a loss‐of‐function variant CYP2C19*2 affects clinical profiles of clopidogrel (efficacy and safety). However, data on the impact of a gain‐of‐function variant CYP2C19*17 on the response to that drug seem to be less consistent. Objectives: To systematically summarize all available clinical data assessing the role of the CYP2C19*17 variant in patients taking clopidogrel. Methods: A literature search was conducted and a meta‐analysis was performed for 11 eligible studies. The endpoints included the major adverse cardiovascular events (MACE, representing non‐fatal myocardial infarction, stroke, revascularization, or death), bleeding events, mortality, stent thrombosis and high platelet reactivity (HPR). Results: Data from six clinical studies demonstrated that carriers of the CYP2C19*17 variant had a marked protection against recurrent cardiovascular events in patients with coronary artery disease compared with non‐carriers, as measured by a 16% decrease in the incidence of MACE (10.0% vs. 11.9%; OR, 0.82; 95% CI, 0.72–0.94; P = 0.005). On the other hand, carriers had an increased risk of developing bleeding as expected (8.0% vs. 6.5%; OR, 1.25; 95% CI, 1.07–1.47; P = 0.006; four studies). Moreover, the presence of the CYP2C19*17 variant might lead to increased response to clopidogrel, as shown by a marked lower prevalence of HPR in carriers than in non‐carriers (37.9% vs. 50.8%; OR, 0.60; 95% CI, 0.45–0.79; P = 0.0003; three studies). Conclusions: Carriers of the CYP2C19*17 variant have greater therapeutic responsiveness to clopidogrel than non‐carriers, but they have an increased risk of developing bleeding as well.     

Combined influence of proton‐pump inhibitors,calcium‐channel blockers and CYP2C19*2 on on‐treatment platelet reactivity and on the occurrence of atherothrombotic events after percutaneous coronary intervention

Summary. Background: The carriage of CYP2C19*2 and the use of proton‐pump inhibitors (PPIs) and calcium‐channel blockers (CCBs) has been associated with the diminished efficacy of clopidogrel. However, previous studies have only assessed the isolated impact of these risk factors for clopidogrel poor response. Objectives: The aim of the present study was to investigate the impact of the combined presence of three risk factors for clopidogrel poor response, that is, the use of CCBs, PPIs and the carriage of CYP2C19*2, on on‐treatment platelet reactivity and the occurrence of atherothrombotic events in 725 patients on dual antiplatelet therapy undergoing elective coronary stenting. Methods: In a prospective, follow‐up study, on‐treatment platelet reactivity was quantified using ADP‐induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay. The clinical study endpoint was the composite of all‐cause mortality, myocardial infarction, stent thrombosis and stroke at 1 year after stenting. Results: Patients with either one or more than one risk factor exhibited increased platelet reactivity (mean relative increase one risk factor: 11% and > 1 risk factor: 22%, respectively). Sixty‐four events occurred during follow‐up (8.8% of the study population). Patients with one risk factor for clopidogrel poor response did not have an increased risk of the composite endpoint. However, patients using both CCBs and PPIs and carriers of CYP2C19*2 who used CCBs had a statistically significant increased risk of the composite endpoint [hazard ratio(HR)_adj 2.2 95% CI, 1.0–5.3, P = 0.044 and HR_adj 3.3 95% CI, 1.1–9.8, P = 0.032, respectively]. Conclusions: The presence of more than one of the three investigated risk factors for clopidogrel poor response is associated with an increased risk of adverse cardiovascular events within 1 year after elective coronary stenting.     

Clinical implications of drug–drug interactions with P2Y12 receptor inhibitors

Polypharmacy in patients undergoing coronary artery stenting or in those presenting with an acute coronary syndrome is common. Nevertheless, the risk of drug–drug interactions in patients treated simultaneously with P2Y₁₂ receptor inhibitors is less well considered in routine clinical practice. Whereas the irreversible P2Y₁₂ receptor inhibitors clopidogrel and prasugrel are prodrugs requiring cytochrome P450 (CYP) enzymes for metabolic activation, such activation is not necessary for the direct‐acting reversible P2Y₁₂ receptor inhibitor ticagrelor. Several drugs frequently used in cardiology have been shown to interact with the metabolism of P2Y₁₂ receptor inhibitors in pharmacodynamic studies. Whereas several drug–drug interactions have been described for clopidogrel and ticagrelor, prasugrel seems to have a low potential for drug–drug interactions. The clinical implications of these interactions have raised concern. In general, concomitant administration of P2Y₁₂ receptor antagonists and strong inhibitors or inducers of CYP3A/CYP2C19 should be performed with caution in patients treated with clopidogrel/ticagrelor. Under most circumstances, clinicians have the option of prescribing alternative drugs with less risk of drug–drug interactions when used concomitantly with P2Y₁₂ receptor inhibitors.     

Pharmacokinetic basis of the antiplatelet action of prasugrel

Prasugrel is the most recent development of thienopyridine-type antiplatelet drugs. Like the earlier-generation thienopyridines, i.e. ticlopidine and clopidogrel, prasugrel is also an inactive prodrug that requires metabolic processing in vivo to generate the active antiplatelet metabolite. The efficacy of this bioactivation is the key determinant for the pharmacodynamic potency of the compound, i.e. the irreversible blockade of the platelet P2Y12-ADP receptor. Prasugrel is rapidly absorbed from the gut. After oral administration of standard-loading doses of 60 mg, maximum plasma levels of the active metabolite are achieved within 1 h, effective, maximum inhibition of platelet aggregation at 1-2 h. Bioconversion of prasugrel into the active metabolite requires two metabolic steps that occur in sequence. The first is the generation of a thiolactone-intermediate, mainly by carboxyesterases-2 in the intestine, the second the cytochrome (CYP)-dependent conversion of the thiolactone into the active metabolite. This second step involves several cytochromes, most notably CYP3A4, CYP2C19, CYP2B6, and CYP2C9. The enzymatic generation of the active metabolite of prasugrel is much more effective than that of clopidogrel where only about 5% of oral clopidogrel is transformed into the active compound by two-step CYP-dependent procedures. About 70% of prasugrel metabolites are excreted in the urine and 30% in the feces. The molar potency of the respective active metabolites of prasugrel and clopidogrel is identical. Thus, the more rapid onset, higher potency and lower interindividual variability of antiplatelet effects of prasugrel as compared to clopidogrel in vivo are entirely because of its more efficient pharmacokinetics.     

CYP2C19基因多态性与冠心病患者氯吡格雷疗效的相关性研究

目的对CYP2C19基因多态性与冠心病患者氯吡格雷疗效的相关性进行分析探讨,为今后的临床工作,提供有价值的参考信息。方法选取2015年1月至2016年1月该院收治的,拟接受经皮冠状动脉介入术(PCI)进行治疗的冠心病患者128例作为研究对象,对其均开展氯吡格雷治疗,负荷剂量为300mg,维持剂量为75mg,将受试者分成氯吡格雷抵抗组与反应组,对比两组患者药物代谢CYP2C19基因型,观察CYP2C19基因型对氯吡格雷反应性的影响。结果该组受试者中,氯吡格雷抵抗者27例,检出CYP2C19慢代谢基因型携带者共计16例,慢代谢基因型患者VASP-PRI与快代谢基因型、中间代谢基因型患者比较,差异有统计学意义(P0.05);氯吡格雷抵抗组与氯吡格雷反应组临床不良终点事件发生率比较差异有统计学意义(P0.05)。结论氯吡格雷抵抗的危险因素中,包括CYP2C19慢代谢基因型,氯吡格雷抵抗会使临床不良终点事件发生风险增加,临床应对其给予足够的重视。     

Pharmacogenetics of esomeprazole or rabeprazole‐based triple therapy in Helicobacter pylori eradication in Hong Kong non‐ulcer dyspepsia Chinese subjects

Objective: Our study aimed to assess the effectiveness of esomeprazole or rabeprazole in combination with amoxicillin and clarithromycin for the eradication of Helicobacter pylori in Hong Kong non‐ulcer dyspepsia (NUD) patients. Methods: A prospective clinical trial was conducted at the Alice Ho Miu ling Nethersole Hospital outpatient endoscopy center from June 2004 to December 2005. Participants received amoxicillin 1 g, clarithromycin 500 mg, and, esomeprazole 20 mg (EAC) or rabeprazole 20 mg (RAC), all given twice daily for 1 week. The H. pylori status was determined by the [¹³C] urea breath test at least 4 weeks after completion of the treatment. Mutation status of CYP2C19 in exon 4 and exon 5 associated with the poor metabolizer phenotype was determined. Results: The intention‐to‐treat eradication rates in patients treated with RAC and EAC were 77% and 84·6% respectively, and per protocol‐based eradication rates were 83·7% and 88·9% respectively. The eradication rates did not vary with CYP2C19 phenotype found. For clarithromycin‐sensitive strains, the cure rates were statistically significant regardless of CYP2C19 polymorphism (P < 0·0001). Conclusion: Triple therapy with either EAC or RAC is effective for Hong Kong Chinese NUD patients with H. pylori infection. Success eradication was related to clarithromycin resistance and not CYP2C19 genotype.     

Influence of CYP450 Enzymes,CES1, PON1, ABCB1, and P2RY12 Polymorphisms on Clopidogrel Response in Patients Subjected to a Percutaneous Neurointervention

PurposeClopidogrel is a thienopyridine prodrug that inhibits platelet aggregation. It is prescribed to prevent atherothrombotic and thromboembolic events in patients receiving a stent implant in carotid, vertebral, or cranial arteries. The influence of cytochrome P-450 (CYP) 2C19 on the response to clopidogrel has been widely studied; however, the effect of other genes involved in clopidogrel absorption and metabolism has not been established in this cohort of patients.MethodsThis observational retrospective study assessed the antiplatelet response and the prevalence of hemorrhagic or ischemic events after percutaneous neurointervention in clopidogrel-treated patients, related to 35 polymorphisms in the genes encoding the clopidogrel-metabolizing enzymes (CYP2C19, CYP1A2, CYP2B6, CYP2C9, CYP2C9, CYP3A4, CYP3A5, carboxylesterase-1 [CES1], and paraoxonase-1 [PON1]), P-glycoprotein transporter (ABCB1), and platelet receptor P2Y₁₂. Polymorphisms were analyzed by quantitative real-time polymerase chain reaction and matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry. Antiplatelet response was documented with the VerifyNow system (Accriva, San Diego, California).FindingsWe confirmed that CYP2C19 is the most important enzyme involved in clopidogrel response. The carriage of the CYP2C19*2 allele was strongly associated with hyporesponse to clopidogrel, while the CYP2C19*17 allele was a protective factor for the development of ischemic events (odds ratio = 0.149; P = 0.002) but a risk factor for bleeding (odds ratio = 3.60; P = 0.038). Patients carrying ABCB1 mutated alleles showed lower aggregation values, suggesting that clopidogrel absorption is influenced by P-glycoprotein. In fact, the percentage of responders was significantly higher in the group carrying the mutated haplotype compared to the wild type (80.8% vs 43.3%; P = 0.009). Patients with the CES1 G143E C/T genotype showed a considerably lower, aggregation value versus wild-type patients, although the difference was not significant likely due to the small sample size (59.0 [21.2] vs 165.2 [86.0] PRU; P = 0.084), which suggests an increased active metabolite formation. No relationship was found between polymorphisms in other CYP genes, PON1, or P2RY12 and response to clopidogrel in patients subjected to neurointervention procedures.ImplicationsTherapeutic guidelines recommend that CYP2C19 intermediate and poor metabolizers with acute coronary syndromes undergoing percutaneous coronary intervention receive an alternative antiplatelet therapy; however, genotype-guided therapy is not a standard recommendation for neurovascular conditions. This is the first study to carry out a joint analysis of CYP2C19 and other genes involved in clopidogrel treatment in patients receiving percutaneous neurointervention. Our findings support routine genotyping in clopidogrel-treated patients. Moreover, we encourage considering an alternative antiplatelet therapy in CYP2C19 intermediate, poor and ultrarapid metabolizers. Additionally, ABCB1 polymorphisms could be considered for a better pharmacogenetic approach.     

Randomized Assessment of Ticagrelor Versus Prasugrel Antiplatelet Effects in Patients With Diabetes

OBJECTIVE

It has been postulated that prasugrel might be the preferred treatment option in diabetes mellitus (DM) patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). We aimed to compare the pharmacodynamic action of ticagrelor versus prasugrel.

RESEARCH DESIGN AND METHODS

In a prospective, single-center, single-blind, crossover study, 30 consecutive ACS patients with DM who had been pretreated with clopidogrel were randomized to either 90 mg ticagrelor twice daily or 10 mg prasugrel once daily with a 15-day treatment period. Platelet reactivity (PR) was assessed with the VerifyNow P2Y12 function assay, measured in P2Y12 reaction units (PRU).

RESULTS

PR was significantly lower after ticagrelor (45.2 PRU [95% CI 27.4–63.1]) compared with prasugrel (80.8 PRU [63.0–98.7]), with a least squares mean difference of –35.6 PRU (−55.2 to −15.9, P = 0.001). High PR rate was 0% for ticagrelor and 3.3% for prasugrel (P = 1.0).

CONCLUSIONS

In DM patients with ACS who had been pretreated with clopidogrel and who undergo PCI, ticagrelor achieves a significantly higher platelet inhibition than prasugrel. Both antiplatelet agents effectively treat high PR. The relevance of these findings to the clinical efficacy and safety of ticagrelor and prasugrel in DM patients needs further elucidation.Patients with diabetes mellitus (DM) suffering from acute coronary syndrome (ACS) and/or undergoing percutaneous coronary intervention (PCI) have an increased platelet reactivity (PR) and prothrombotic potential, a lower response to clopidogrel, and a higher risk of cardiovascular complications and recurrent atherothrombotic events than non-DM patients (1–8).Prasugrel and ticagrelor are newer and more potent than clopidogrel antiplatelet agents, which have been introduced recently into our armamentarium while treating ACS patients undergoing PCI (9,10). In the Prasugrel Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS-3) study, in patients with DM and coronary artery disease (CAD), prasugrel provided a higher inhibitory platelet activity than high-dose clopidogrel (11). A prespecified, subgroup analysis of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) showed that prasugrel significantly reduced the incidence of the composite of cardiovascular death, myocardial infarction, and stroke compared with clopidogrel (12.2 and 17.0%, respectively, HR 0.70; P < 0.001) among DM patients, although without significant DM status-by-treatment interaction (12). Of note, no benefit on mortality was observed with prasugrel over clopidogrel. Furthermore, in the subgroup analyses of the Platelet Inhibition and Patient Outcomes (PLATO) trial, the reduction in the primary composite end point, all-cause mortality, and stent thrombosis with no increase in major bleeding in DM patients by ticagrelor was consistent with the overall cohort (3,13). While interpreting the above subanalyses, it has been proposed that prasugrel may be the preferred treatment option in DM patients (14), although a word of caution has been raised by others for comparison between PLATO and TRITON regarding early ischemic events in such patients (3).There are no direct clinical outcome comparisons of ticagrelor versus prasugrel. In a pharmacodynamic comparison of ticagrelor versus prasugrel in ACS patients undergoing PCI and exhibiting high PR (HPR) while on clopidogrel, ticagrelor reduced PR to a lower level than prasugrel (15). In ST segment elevation myocardial infarction patients undergoing primary PCI, both ticagrelor and prasugrel appeared similarly effective in reducing PR during the first 24 h, with lower PR achieved with ticagrelor than prasugrel at day 5 (16). In the current study, we aimed to compare the pharmacodynamic action of ticagrelor versus prasugrel in DM patients with ACS undergoing PCI who had been pretreated with clopidogrel.     

Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS‐PCI study

Summary. Background: Prognostic values of genotyping and phenotyping for assessment of clopidogrel responsiveness have been shown in independent studies.Objectives: To compare different assays for prediction of events during long‐term follow‐up.Methods: In this prospective cohort study polymorphisms of CYP2C19*2 and CYP2C19*17 alleles, vasodilator‐stimulated phosphoprotein phosphorylation (VASP) assay, multiple electrode aggregometry (MEA), cone and platelet analyser (CPA) and platelet function analyser (PFA‐100) were performed in 416 patients undergoing percutaneous coronary intervention. The rates of events were recorded during a 12‐month follow‐up.Results: Platelet aggregation by MEA predicted stent thrombosis (2.4%) better (c‐index = 0.90; P < 0.001; sensitivity = 90%; specificity = 83%) than the VASP assay, CPA or PFA‐100 (c‐index < 0.70; P > 0.05; sensitivity < 70%; specificity < 70% for all) or even the CYP2C19*2 polymorphism (c‐index < 0.56; P > 0.05; sensitivity = 30%; specificity = 71%). Survival analysis indicated that patients classified as poor responders by MEA had a substantially higher risk of developing stent thrombosis or MACE than clopidogrel responders (12.5% vs. 0.3%, P < 0.001, and 18.5% vs. 11.3%, P = 0.022, respectively), whereas poor metabolizers (CYP2C19*1/*2 or *2/*2 carriers) were not at increased risks (stent thrombosis, 2.7% vs. 2.5%, P > 0.05; MACE, 13.5% vs. 12.1%, P = 0.556). The incidence of major bleedings (2.6%) was numerically higher in patients with an enhanced vs. poor response to clopidogrel assessed by MEA (4% vs. 0%) or in ultra‐metabolizers vs. regular metabolizers (CYP2C19*17/*17 vs. CYP2C19*1/*1; 9.5% vs. 2%). The classification tree analysis demonstrated that acute coronary syndrome at hospitalization and diabetes mellitus were the best discriminators for clopidogrel responder status.Conclusions: Phenotyping of platelet response to clopidogrel was a better predictor of stent thrombosis than genotyping.     

The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance

We evaluated the effect of the CYP2C19 genotype on the pharmacokinetics and pharmacodynamcis of clopidogrel. Twenty-four subjects were divided into three groups on the basis of their CYP2C19 genotype: homozygous extensive metabolizers (homoEMs, n = 8), heterozygous EMs (heteroEMs, n = 8), and poor metabolizers (PMs, n = 8). After a single 300-mg loading dose of clopidogrel on day 1, followed by a 75-mg daily maintenance dose from days 2 to 7, we measured the plasma levels of clopidogrel and assessed the antiplatelet effect as pharmacodynamics. The mean clopidogrel area under the curve (AUC) for PMs was 1.8- and 2.9-fold higher than that for heteroEMs and homoEMs, respectively (P = 0.013). The mean peak plasma concentration in PMs was 1.8- and 4.7-fold higher than that of heteroEMs and homoEMs, respectively (P = 0.008). PMs exhibited a significantly lower antiplatelet effect than heteroEMs or homoEMs (P < 0.001). From these findings it is clear that the CYP2C19 genotype affects the plasma levels of clopidogrel and modulates the antiplatelet effect of clopidogrel.     

Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel

BACKGROUND: Thienopyridines are metabolized to active metabolites that irreversibly inhibit the platelet P2Y(12) adenosine diphosphate receptor. The pharmacodynamic response to clopidogrel is more variable than the response to prasugrel, but the reasons for variation in response to clopidogrel are not well characterized. OBJECTIVE: To determine the relationship between genetic variation in cytochrome P450 (CYP) isoenzymes and the pharmacokinetic/pharmacodynamic response to prasugrel and clopidogrel. METHODS: Genotyping was performed for CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP3A4 and CYP3A5 on samples from healthy subjects participating in studies evaluating pharmacokinetic and pharmacodynamic responses to prasugrel (60 mg, n = 71) or clopidogrel (300 mg, n = 74). RESULTS: In subjects receiving clopidogrel, the presence of the CYP2C19*2 loss of function variant was significantly associated with lower exposure to clopidogrel active metabolite, as measured by the area under the concentration curve (AUC(0-24); P = 0.004) and maximal plasma concentration (C(max); P = 0.020), lower inhibition of platelet aggregation at 4 h (P = 0.003) and poor-responder status (P = 0.030). Similarly, CYP2C9 loss of function variants were significantly associated with lower AUC(0-24) (P = 0.043), lower C(max) (P = 0.006), lower IPA (P = 0.046) and poor-responder status (P = 0.024). For prasugrel, there was no relationship observed between CYP2C19 or CYP2C9 loss of function genotypes and exposure to the active metabolite of prasugrel or pharmacodynamic response. CONCLUSIONS: The common loss of function polymorphisms of CYP2C19 and CYP2C9 are associated with decreased exposure to the active metabolite of clopidogrel but not prasugrel. Decreased exposure to its active metabolite is associated with a diminished pharmacodynamic response to clopidogrel.     

冠心病患者CYP2C19基因多态性及临床不良事件发生与氯吡格雷抵抗的关系

目的通过分析经皮冠状动脉介入治疗(PCI)术后冠心病患者的CYP2C19基因型结果、临床相关危险因素和主要心血管不良事件发生情况与氯吡格雷抵抗的关系,探讨影响氯吡格雷抵抗发生、发展的因素,为临床治疗提供有效依据。方法收集2017年1月至2018年12月该院收治并进行过基因检测的346例冠心病患者资料,分析其CYP2C19基因型和代谢型分布特征,筛选出251例使用氯吡格雷的PCI术后冠心病患者,进行血小板聚集功能试验检测,根据血小板最大聚集率(MAR)分为氯吡格雷敏感组(MAR<50%)和氯吡格雷抵抗组(MAR≥50%)。利用荧光PCR法进行CYP2C19基因多态性检测,根据基因型结果分为快代谢型(*1/*1)、中代谢型(*1/*2、*1/*3)和慢代谢型(*2/*2、*2/*3、*3/*3)。比较氯吡格雷抵抗组与氯吡格雷敏感组不同代谢型的患者比例、相关危险因素情况及临床心血管不良事件发生情况。结果慢代谢型患者的MAR较中代谢型、快代谢型患者高,差异均有统计学意义(P<0.05)。入选的251例患者中,氯吡格雷抵抗组CYP2C19代谢型分别为快代谢型38例(34.5%)、中代谢型57例(51.8%)、慢代谢型15例(13.6%),氯吡格雷抵抗组与氯吡格雷敏感组在快代谢型中的患者比例差异有统计学意义(P<0.05)。氯吡格雷抵抗组的高血压患者比例(91.8%)与氯吡格雷敏感组(63.8%)比较,差异有统计学意义(P<0.05)。氯吡格雷抵抗组临床心血管不良事件发生率(94.5%)高于氯吡格雷敏感组(84.4%),差异有统计学意义(P <0.05)。结论CYP2C19基因突变和高血压可能是氯吡格雷抵抗发生的两个重要影响因素,并且氯吡格雷抵抗增加了PCI术后冠心病患者临床心血管不良事件发生的风险。     

基于武汉地区PCI术后患者CYP2C19基因多态性指导氯吡格雷个体化用药的研究

目的 研究CYP2C19基因多态性,分析经皮冠状动脉介入治疗(PCI)术后氯吡格雷中、慢代谢患者个体化用药的疗效差异,为PCI术后患者个体化用药提供参考依据.方法 使用荧光定量PCR法测定该院328例PCI术后患者CYP2C19基因型,分析年龄、性别与CYP2C19基因多态性的关系及不同地区汉族冠心病患者代谢表型差异,...