Should We Perform Genetic Testing on Antiplatelet Therapy?
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor such as clopidogrel, prasugrel, or ticagrelor is the current mainstay of treatment in patients with acute coronary syndromes (ACS).1 However, within the past decade, a substantial variability in pharmacodynamic action of clopidogrel has given rise to concerns and debate.2 Approximately 20-30% of patients with ACS show an inadequate response to clopidogrel, depending on the platelet function assay used and depending on the time point of testing. The observed variability in platelet inhibition in patients treated with standard-dose clopidogrel is related to many clinical factors but also partly explained by genetic polymorphisms encoding CYP2C19, the hepatic enzyme involved in biotransformation of clopidogrel, to its active metabolite.3 A single-nucleotide polymorphism, the CYP2C19 618G>A*2 allelic variant, encoding for a cryptic splice site resulting in complete loss of CYP2C19 enzyme activity, is a key determinant associated with reduced clopidogrel conversion (loss-of-function (LoF) allele) and subsequent high-on-clopidogrel platelet reactivity.4-7 CYP2C19*2 and CYP2C19*3 are the most common LoF alleles. The other known LoF alleles (CYP2C19*4, *5, *6, *7, and *8) are much less common (<1% allelic frequency each)8 and have not been adequately evaluated in clinical studies. Individuals who are heterozygous for LoF alleles are intermediate metabolizers, whereas those who are homozygous are poor metabolizers of clopidogrel. On-treatment platelet reactivity levels (phenotype) as well as genetic risk factors such as CYP2C19*2 (genotype) have shown a strong and significant association with ischemic risk (especially stent thrombosis) in patients with ACS undergoing percutaneous coronary intervention (PCI).7,9-10 There is evidence for a gene-dose effect as well.9
Of note, polymorphisms within the CYP2C19 system comprise not only LoF alleles but also a gain-of-function (GoF) mutation (CYP2C19*17). This allelic variant, a C806T mutation in exon 5, is responsible for increased catalytic activity that is most likely due to a higher transcription rate of the gene. An association of CYP2C19*17 carrier status with risk of bleeding in clopidogrel-treated patients was first described in a large registry cohort and was confirmed later in a genetic substudy of the PLATO (Platelet Inhibition and Patient Outcomes) trial.11,12
In 2010, the US Food and Drug Administration announced a boxed warning on clopidogrel stating that the drug has a reduced effect in patients based on their CYP2C19 genotype.13 However, it is known that genetic polymorphisms account only for 5.2-12% of the variation of adenosine diphosphate-induced platelet aggregation in PCI patients, with other factors collectively explaining >80% of the variation.14 This raises the question of whether routine genetic testing in clopidogrel-treated patients is valuable, especially in those patients with ACS. Additionally, this question remains: does a role exist for genotyping in patients with ACS treated with the new and potent P2Y12 inhibitors: prasugrel and ticagrelor.
Point-of-Care Genetic Testing in Patients With ACS
Individualized treatment based on rapid gene profiling is now feasible because easy-to-use and validated bedside systems for genotyping have become broadly available and affordable.15 Two point-of-care CYP2C19 genotyping assays, the Spartan RX (Spartan Bioscience, Inc.; Ontario, Canada) and the VERIGENE (Luminex Corporation; Austin, TX) assays, identify the two most common LoF alleles (CYP2C19*2 and *3) and the GoF allele (CYP2C19*17). Different studies reported good reproducibility of CYP2C19 genotyping methods and high levels of inter-assay agreement.15,16 The RAPID-GENE (Reassessment of Anti-Platelet Therapy Using an Individualized Strategy Based on Genetic Evaluation) study was the first study to demonstrate that rapid genotyping in patients undergoing coronary stenting could eliminate high-on-clopidogrel platelet reactivity by using prasugrel instead of clopidogrel in CYP2C19*2 allele carriers identified with the Spartan RX (Spartan Bioscience, Inc.; Ontario, Canada) point-of-care platform.15 Overall, the literature suggests that there is prognostic value of CYP2C19 LoF genotyping and ischemic risk prediction. For example, in a large meta-analysis by Mega et al., a significant increase in the risk of both stent thrombosis (hazard ratio [HR] 2.81; 95% confidence interval [CI], 1.81-4.37) and major adverse cardiac events (HR 1.57; 95% CI, 1.13-2.16) in PCI-treated carriers of LoF alleles was observed.9 However, there is no evidence so far for individualizing antiplatelet therapy for PCI-treated patients with stable coronary artery disease or ACS based on CYP2C19 genotyping.
With regard to medically managed patients with ACS, in a pre-specified pharmacogenetic substudy (n = 5,736 patients) from the TRILOGY-ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial, the authors reported that CYP2C19 metabolizer status was not associated with the composite outcome of cardiovascular death, myocardial infarction (MI), or stroke in medically managed patients with ACS treated with clopidogrel or prasugrel (HR 0.86; 95% CI, 0.74-1.02 for the entire study cohort. HR 0.91; 95% CI, 0.73-1.14 for clopidogrel-treated patients).17 These findings do not support CYP2C19 genetic testing in a medically managed ACS population. Also with regard to GoF alleles, there is no evidence for treatment alteration (de-escalation) based on rapid gene profiling so far.
Notably, CYP polymorphisms do not appear to have any influence on prasugrel bioactivation. Additionally, genetic variables contributing to clinical outcomes of patients treated with the potent P2Y12 inhibitors prasugrel or ticagrelor have not been identified. Large subgroups of patients enrolled in the large-scale phase III clinical outcome studies TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With PrasugrelThrombolysis In Myocardial Infarction) (prasugrel) and PLATO (ticagrelor) consented for additional genetic analysis. The observed net clinical benefit of prasugrel or ticagrelor over clopidogrel was not affected by carriage of CYP2C19 LoF alleles.4,12 At present, there are no data supporting any impact of genetic polymorphisms in pharmacokinetics of prasugrel or ticagrelor on clinical outcomes of patients.
Ongoing Studies and Perspective
Because absence of proof is not proof of absence, there are several large-scale and well-designed clinical trials ongoing at the moment that aim to answer the question whether tailoring antiplatelet therapy based on CYP2C19 genotyping provides any benefit. The TAILOR-PCI (Tailored Antiplatelet Initiation to Lesson Outcomes Due to Decreased Clopidogrel Response After Percutaneous Coronary Intervention) trial, with an estimated enrolment of 5,270 patients with either ACS or stable coronary artery disease, randomizes patients to a conventional arm versus a CYP2C19 genotype-based (point-of-care SPARTAN RX assay [Spartan Bioscience, Inc.; Ontario, Canada]) antiplatelet therapy approach with application of ticagrelor 90 mg bid in CYP2C19*2 or *3 carriers. The primary endpoint will include cardiovascular mortality, non-fatal MI, non-fatal stroke, severe recurrent ischemia, and stent thrombosis. The estimated study completion date is March 2020. In addition, the Dutch POPular Genetics (Cost-effectiveness of CYP2C19 Genotype Guided Treatment With Antiplatelet Drugs in Patients With ST-segment-elevation Myocardial Infarction Undergoing Immediate PCI With Stent Implantation: Optimization of Treatment) trial randomizes 2,700 patients with ST-segment elevation MI to a CYP2C19 genotype-guided therapy using the point-of-care SPARTAN RX (Spartan Bioscience, Inc.; Ontario, Canada) device or conventional prasugrel/ticagrelor therapy. In the genotyping group, wildtype patients receive clopidogrel, and patients carrying one or two *2 or *3 LoF alleles receive ticagrelor or prasugrel. Primary net clinical benefit (composite of death, MI, definite stent thrombosis, stroke, and PLATO major bleeding at 1 year), safety, and cost-effectiveness will be analyzed.18 Moreover, the multicenter TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment For Acute Coronary Syndromes Trial),19 focusing on a platelet function testing-guided de-escalation of antiplatelet treatment in the early maintenance phase after ACS, features a CYP2C19 genotyping substudy (point-of-care SPARTAN RX assay [Spartan Bioscience, Inc.; Ontario, Canada]) evaluating CYP2C19 LoF and GoF allele status, the level of platelet reactivity, and patient outcome. In concert, these ongoing trials now target high-risk populations and will provide important and interesting insights into this topic. Upcoming evidence may help answer the question of whether genetic testing could be useful for guidance of antiplatelet treatment.
- There is a large body of evidence in support of a prognostic value of CYP2C19 genotyping and outcomes of ACS patients.7,9
- Easy-to-use point-of-care CYP2C19 assays, such as the Spartan RX (Spartan Bioscience, Inc.; Ontario, Canada) and the VERIGENE (Luminex Corporation; Austin, TX) assays, identify common LoF (CYP2C19*2 and *3) and GoF (CYP2C19*17) alleles with good reproducibility and high levels of inter-assay agreement.15,16
- There are several large-scale and well-designed randomized clinical trials ongoing that aim to answer the question of whether tailoring antiplatelet therapy based on CYP2C19 genotyping provides any benefit, for example the TAILOR-PCI and POPular Genetics trials. The therapeutic strategies evaluated in such trials may help to optimize the antiplatelet treatment of patients with ACS.
- Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37:267-315.
- Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107:2908-13.
- Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 2009;302:849-57.
- Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354-62.
- Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009;373:309-17.
- Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;360:363-75.
- Sibbing D, Stegherr J, Latz W, et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J 2009;30:916-22.
- Scott SA, Sangkuhl K, Stein CM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther 2013;94:317-23.
- Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA 2010;304:1821-30.
- Aradi D, Kirtane A, Bonello L, et al. Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J 2015;36:1762-71.
- Sibbing D, Koch W, Gebhard D, et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 2010;121:512-8.
- Wallentin L, James S, Storey RF, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 2010;376:1320-8.
- Holmes DR Jr, Dehmer GJ, Kaul S, Leifer D, O'Gara PT, Stein CM. ACCF/AHA clopidogrel clinical alert: approaches to the FDA "boxed warning": a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2010;56:321-41.
- Hochholzer W, Trenk D, Fromm MF, et al. Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J Am Coll Cardiol 2010;55:2427-34.
- Roberts JD, Wells GA, Le May MR, et al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet 2012;379:1705-11.
- Erlinge D, James S, Duvvuru S, et al. Clopidogrel metaboliser status based on point-of-care CYP2C19 genetic testing in patients with coronary artery disease. Thromb Haemost 2014;111:943-50.
- Doll JA, Neely ML, Roe MT, et al. Impact of CYP2C19 Metabolizer Status on Patients With ACS Treated With Prasugrel Versus Clopidogrel. J Am Coll Cardiol 2016;67:936-47.
- Bergmeijer TO, Janssen PW, Schipper JC, et al. CYP2C19 genotype-guided antiplatelet therapy in ST-segment elevation myocardial infarction patients-Rationale and design of the Patient Outcome after primary PCI (POPular) Genetics study. Am Heart J 2014;168:16-22.e1.
- Sibbing D, Aradi D, Jacobshagen C, et al. A randomised trial on platelet function-guided de-escalation of antiplatelet treatment in ACS patients undergoing PCI. Rationale and design of the Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes (TROPICAL-ACS) Trial. Thromb Haemost 2017;117:188-95.
Keywords: Acute Coronary Syndrome, Platelet Aggregation Inhibitors, Aspirin, Platelet Aggregation, Coronary Artery Disease, Blood Platelets, Purinergic P2Y Receptor Antagonists, Adenosine Diphosphate, Polymorphism, Single Nucleotide, Myocardial Infarction, Risk Factors, Ticlopidine, Platelet Function Tests, Adenosine, Percutaneous Coronary Intervention, Stroke, Biotransformation, Phenotype, Stents, Thrombosis, Outcome Assessment, Health Care, Polyethylene Glycols
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