CYP2C19 Genotype-guided Antiplatelet Therapy Research Articles

Optimizing endovascular therapy for large vessel occlusion using CYP2C19 genotype-guided antiplatelet therapy: a case report

Optimizing endovascular therapy for large vessel occlusion using CYP2C19 genotype-guided antiplatelet therapy: a case report

Role of Cyp2c19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

Identification of a reliable discriminatory test to accurately stratify patient responses to antiplatelet therapy following coronary revascularization has become increasingly desirable to optimize therapeutic efficacy and safety. The expansion of platelet function testing to include genotype assessment has been an evolutionary journey, initially fraught with confounding results. However, more recent and rigorous data analysis suggests that genotype testing- guided, tailored antiplatelet therapy may hold promise in optimizing treatment of patients after coronary intervention. Current evidence increasingly supports the use of genotype guided CYP2C19 testing to better match the post coronary intervention patient with the most efficacious and least risky antiplatelet inhibitor. The risk stratification of poor, intermediate, and good metabolizers of these drugs with such testing promises to yield clinical dividends in terms of morbidity, mortality and cost control, in this growing patient population.

Implementation of clopidogrel pharmacogenetic clinical decision support for a preemptive return of results program.

To describe our experiences implementing and iterating CYP2C19 genotype-guided clopidogrel pharmacogenetic clinical decision support (CDS) tools over time in the setting of a large health system-wide, preemptive pharmacogenomics program. Clopidogrel-treated patients who are genetically predicted cytochrome P450 isozyme 2C19 (CYP2C19) intermediate or poor metabolizers have an increased risk of atherothrombotic events, some of which can be life-threatening. The Clinical Pharmacogenetics Implementation Consortium provides guidance for the use of clopidogrel based on CYP2C19 genotype in patients with cardiovascular and cerebrovascular diseases. Our multidisciplinary team implemented an automated, interruptive alert that fires when clopidogrel is ordered or refilled for biobank participants with structured CYP2C19 intermediate or poor metabolizer genomic indicators in the electronic health record. The implementation began with a narrow cardiovascular indication and setting and was then scaled in 4 primary dimensions: (1) clinical indication; (2) availability across health-system locations; (3) care venue (e.g., inpatient vs outpatient); and (4) provider groups (eg, cardiology and neurology). We iterated our approach over time based on evolving clinical evidence and proactive strategies to optimize CDS maintenance and sustainability. A key facilitator of expansion was socialization of the broader pharmacogenomics initiative among our academic medical center community, accompanied by clinician acceptance of pharmacogenetic alerts in practice. A multidisciplinary collaboration is recommended to facilitate the use of CYP2C19 genotype-guided antiplatelet therapy in patients with cardiovascular and cerebrovascular diseases. Evolving clopidogrel pharmacogenetic evidence necessitates thoughtful iteration of implementation efforts and strategies to optimize long-term maintenance and sustainability.

Pharmacogenetics of P2Y12 receptor inhibitors.

Oral P2Y12 inhibitors are commonly prescribed for cardiovascular disease and include clopidogrel, prasugrel, and ticagrelor. Each of these drugs has its strengths and weaknesses. Prasugrel and ticagrelor are more potent inhibitors of platelet aggregation and were shown to be superior to clopidogrel in preventing major adverse cardiovascular events after an acute coronary syndrome and percutaneous coronary intervention (PCI) in the absence of genotyping. However, both are associated with an increased risk for non-coronary artery bypass-related bleeding. Clopidogrel is a prodrug requiring bioactivation, primarily via the CYP2C19 enzyme. Approximately 30% of individuals have a CYP2C19 no function allele and decreased or no CYP2C19 enzyme activity. Clopidogrel-treated carriers of a CYP2C19 no function allele have decreased exposure to the clopidogrel active metabolite and lesser inhibition of platelet aggregation, which likely contributed to reduced clopidogrel efficacy in clinical trials. The pharmacogenetic data for clopidogrel are most robust in the setting of PCI, but evidence is accumulating for other indications. Guidance is available from expert consensus groups and regulatory agencies to assist with integrating genetic information into P2Y12 inhibitor prescribing decisions, and CYP2C19 genotype-guided antiplatelet therapy after PCI is one of the most common examples of clinical pharmacogenetic implementation. Herein, we review the evidence for pharmacogenetic associations with clopidogrel response and outcomes with genotype-guided P2Y12 inhibitor selection and describe guidance to assist with pharmacogenetic implementation. We also describe processes for applying genotype data for P2Y12 inhibitor therapy selection and remaining gaps in the field. Ultimately, consideration of both clinical and genetic factors may guide selection of P2Y12 inhibitor therapy that optimally balances the atherothrombotic and bleeding risks.

Evaluation of race and ethnicity disparities in outcome studies of CYP2C19 genotype-guided antiplatelet therapy.

Dual antiplatelet therapy with a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin remains the standard of care for all patients undergoing percutaneous coronary intervention (PCI). It is well-established that patients carrying CYP2C19 no function alleles have impaired capacity to convert clopidogrel into its active metabolite and thus, are at higher risk of major adverse cardiovascular events (MACE). The metabolism and clinical effectiveness of prasugrel and ticagrelor are not affected by CYP2C19 genotype, and accumulating evidence from multiple randomized and observational studies demonstrates that CYP2C19 genotype-guided antiplatelet therapy following PCI improves clinical outcomes. However, most antiplatelet pharmacogenomic outcome studies to date have lacked racial and ethnic diversity. In this review, we will (1) summarize current guideline recommendations and clinical outcome evidence related to CYP2C19 genotype-guided antiplatelet therapy, (2) evaluate the presence of potential racial and ethnic disparities in the major outcome studies supporting current genotype-guided antiplatelet therapy recommendations, and (3) identify remaining knowledge gaps and future research directions necessary to advance implementation of this precision medicine strategy for dual antiplatelet therapy in diverse, real-world clinical settings.

CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention in Diverse Clinical Settings.

BackgroundStudies have demonstrated increased risk of major atherothrombotic events in CYP2C19 loss‐of‐function (LOF) variant carriers versus non‐carriers treated with clopidogrel after percutaneous coronary intervention (PCI). We sought to evaluate real‐world outcomes with the clinical implementation of CYP2C19‐guided antiplatelet therapy after PCI.Methods and ResultsData from 9 medical centers where genotyping was performed in the setting of PCI were included. Alternative therapy with prasugrel or ticagrelor was recommended for patients with a CYP2C19 LOF variant. The primary outcome was the composite of major atherothrombotic events (all‐cause death, myocardial infarction, ischemic stroke, stent thrombosis, or hospitalization for unstable angina) within 12 months following PCI. Moderate or severe/life‐threatening bleeding within 12 months was a secondary outcome. Among 3342 patients, 1032 (31%) were LOF carriers, of whom 571/1032 (55%) were treated with alternative therapy. In LOF carriers, the rate of major atherothrombotic events was lower in patients treated with alternative therapy versus clopidogrel (adjusted HR, 0.56; 95% CI 0.39–0.82). In those without a LOF allele, no difference was observed (adjusted HR, 1.07; 95% CI 0.71–1.60). There was no difference in bleeding with alternative therapy versus clopidogrel in either LOF carriers or those without a LOF allele.ConclusionsReal‐world data demonstrate lower atherothrombotic risk in CYP2C19 LOF carriers treated with alternative therapy versus clopidogrel and similar risk in those without a LOF allele treated with clopidogrel or alternative therapy. These data suggest that PCI patients treated with clopidogrel should undergo genotyping so that CYP2C19 LOF carriers can be identified and treated with alternative therapy.

Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update.

CYP2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 genotype impacts clopidogrel active metabolite formation. CYP2C19 intermediate and poor metabolizers who receive clopidogrel experience reduced platelet inhibition and increased risk for major adverse cardiovascular and cerebrovascular events. This guideline is an update to the 2013 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of clopidogrel based on CYP2C19 genotype and includes expanded indications for CYP2C19 genotype-guided antiplatelet therapy, increased strength of recommendation for CYP2C19 intermediate metabolizers, updated CYP2C19 genotype to phenotype translation, and evidence from an expanded literature review (updates at www.cpicpgx.org).

Evaluation of race and ethnicity disparities in outcome studies of CYP2C19 genotype-guided antiplatelet therapy

Evaluation of race and ethnicity disparities in outcome studies of CYP2C19 genotype-guided antiplatelet therapy

Effects of aging on clinical outcomes in patients receiving genotype‐guided P2Y12 inhibitor selection after percutaneous coronary intervention

To compare the clinical effectiveness of genotype-guided P2Y12 inhibitor selection following PCI in older patients (≥70 years) and younger patients (<70 years). Single-center, retrospective, cohort study. Risk of major adverse cardiovascular or cerebrovascular events (MACCE), defined as stent thrombosis, ischemic stroke, transient ischemic attack, non-fatal acute coronary syndrome, or cardiovascular death during 12 months after PCI, was compared across genotype and antiplatelet therapy groups by proportional hazards regression in patients ≥70 years and <70 years. 1,469 patients who underwent PCI and had CYP2C19 genotype testing at a single academic medical center. The study population was comprised of 402 (27.4%) ≥70years (older group) and 1067 (72.6%) <70years (younger group). Alternative P2Y12 inhibitors (prasugrel or ticagrelor) were used less often in the older group than the younger group in patients with a CYP2C19 no function allele (55% vs. 67%; p=0.02) and in patients without a no function allele (10% vs. 35%, p<0.001). For patients treated with clopidogrel, MACCE was significantly higher in no function allele carriers compared to those without a no function allele in the older group (19.2% vs. 12.7%; adjusted HR 2.32; 95% CI 1.07-5.05; p=0.03) and the younger group (17.4% vs. 10.4%; adjusted HR 2.01; 95% CI 1.17-3.46; p=0.01). In patients without a no function allele, MACCE risk was similar with clopidogrel compared to prasugrel or ticagrelor in the older group (adjusted HR 0.99; 95% CI 0.44-2.21; p=0.98) and the younger group (adjusted HR 1.12; 95% CI 0.72-1.74; p=0.61). This study suggests important clinical benefits of CYP2C19 genotype-guided antiplatelet therapy after PCI in both younger and older patients.

Analytical validation of GMEX rapid point-of-care CYP2C19 genotyping system for the CHANCE-2 trial

Background and purposeRapid genotyping is useful for guiding early antiplatelet therapy in patients with high-risk nondisabling ischaemic cerebrovascular events (HR-NICE). Conventional genetic testing methods used in CYP2C19 genotype-guided antiplatelet therapy...

Impact of Implementing CYP2C19 Genotype-Guided Antiplatelet Therapy on P2Y12 Inhibitor Selection and Clinical Outcomes in Acute Coronary Syndrome Patients After Percutaneous Coronary Intervention: A Real-World Study in China.

Background: CYP2C19 loss-of-function (LOF) alleles reduce the effectiveness of clopidogrel in patients undergoing percutaneous coronary intervention for acute coronary syndrome. However, the clinical impact of implementing CYP2C19 gene-guided pharmacotherapy is unclear, especially among the Chinese population. The purpose of this study was to evaluate P2Y12 receptor inhibitor selection and clinical outcomes upon implementation of CYP2C19 genotype-guided pharmacotherapy in current clinical practice. Methods: This was a single-center observational cohort study. Adult percutaneous coronary intervention patients who received CYP2C19 genetic testing (*2, *3, *17 alleles) were included. Ticagrelor was recommended for patients with a LOF allele. Factors related to P2Y12 inhibitor selection were determined by logistic regression. The primary endpoint was major cardiac or cerebrovascular adverse events (MACCE) within 12 months. MACCE and clinically significant bleeding events (BARC ≥2) in the LOF-clopidogrel group, non-LOF-clopidogrel group, and non-LOF-ticagrelor group were compared with those in the LOF-ticagrelor group. The inverse probability of treatment weighting (IPTW) was adjusted in a Cox regression analysis to eliminate confounding factors. Results: Among 1,361 patients, 826 (60.7%) had a LOF allele. Patients with a LOF allele were more likely to be prescribed ticagrelor (multivariate-adjusted OR 1.349; 95% CI 1.040 to 1.751; p = 0.024). The MACCE rate was higher in the LOF-clopidogrel group than in the LOF-ticagrelor group (7.8 vs. 4.0%; log-rank p = 0.029; IPTW-adjusted HR 2.138; 95% CI 1.300–3.515). Compared with the LOF-ticagrelor group, the non-LOF-clopidogrel group showed no significant difference in MACCE rate (5.8 vs. 4.0%; log-rank p = 0.272; IPTW-adjusted HR 1.531; 95% CI 0.864–2.714). Among the patients treated with ticagrelor, there was no significant difference in the MACCE rate between the LOF group and non-LOF group (4.3 vs. 4.0%; log-rank p = 0.846; IPTW-adjusted HR 1.184; 95% CI 0.582–2.410). There was no significant difference in the incidence of clinically significant bleeding events among the four groups. Conclusion: This study confirms that efficiently returned CYP2C19 genotype results did partially guide cardiologists to prescribe ticagrelor for patients with a LOF allele, and that clopidogrel had a higher risk of MACCE than ticagrelor in these patients, which provides support for the implementation of CYP2C19 gene-guided antiplatelet therapy in clinical practice.

Clinical Utility of CYP2C19 Genotype-Guided Antiplatelet Therapy in Patients at Risk of Adverse Cardiovascular and Cerebrovascular Events: A Review of Emerging Evidence.

In patients undergoing percutaneous coronary intervention (PCI), the standard of care is dual antiplatelet therapy with a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin. Current clinical practice guidelines now recommend more potent P2Y12 inhibitors (prasugrel or ticagrelor) over clopidogrel in acute coronary syndrome (ACS). However, clopidogrel remains the most commonly prescribed P2Y12 inhibitor in the setting of PCI and is also the preferred agent in the treatment and secondary prevention of stroke. Clopidogrel is a prodrug that requires bioactivation by the CYP2C19 enzyme. It has been shown that clopidogrel use in patients who are CYP2C19 no function allele carriers are associated with impaired antiplatelet inhibition and a higher risk of major adverse cardiovascular and cerebrovascular events. Compared to clopidogrel, prasugrel and ticagrelor clinical response is not impacted by CYP2C19 genotype. Even with a demonstrated increased risk of adverse outcomes in CYP2C19 no function allele carriers treated with clopidogrel, routine implementation of CYP2C19 genotyping to guide antiplatelet therapy selection has remained controversial and has not been widely adopted. Recent results from multiple prospective randomized and nonrandomized clinical trials investigating the use of CYP2C19 genotype-guided antiplatelet therapy following PCI have advanced the evidence base demonstrating the clinical utility of this strategy. Multiple recent studies have examined the effects of CYP2C19 genotype on clopidogrel outcomes in the setting of stroke and neurointerventional procedures. In this review, we discern the clinical utility of using CYP2C19 genotype testing to guide antiplatelet therapy prescribing by evaluating the impact of CYP2C19 genotype-guided selection of antiplatelet therapy on clinical outcomes, summarizing emerging data from cardiovascular and neurology clinical studies, and discussing implications for clinical practice guidelines, remaining knowledge gaps and future research directions.

Economic Evaluations of CYP2C19 Genotype-Guided Antiplatelet Therapy Compared to the Universal Use of Antiplatelets in Patients With Acute Coronary Syndrome: A Systematic Review.

Clopidogrel is widely used after the percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) and requires activation by cytochrome P450 (CYP), primarily CYP2C19. Patients with CYP2C19 loss-of-function alleles are at increased risk of major adverse cardiovascular events, while more expensive novel antiplatelet agents (ticagrelor and prasugrel) are unaffected by the CYP2C19 mutations. This systematic review aims to answer the question about whether overall evidence supports the genotype-guided selection of antiplatelet therapy as a cost-effective strategy in post-PCI ACS. A systematic literature search of PubMed, EMBASE, EconLit, and PharmGKB was done to identify all the economic evaluations related to genotype-guided therapy compared to the universal use of antiplatelets in ACS patients. Quality of Health Economic Studies tool was used for quality assessment. The search identified 13 articles, where genotype-guided treatment was compared to universal clopidogrel, ticagrelor, and/or prasugrel. Six studies showed that genotype-guided therapy was cost-effective compared to universal clopidogrel, while 5 studies showed that it was dominant. One study specified that genotype-guided with ticagrelor is cost-effective only in both CYP2C19 intermediate and poor metabolizers. Genotype-guided therapy was dominant when compared to universal prasugrel, ticagrelor, or both in 5, 1, and 3 studies, respectively. Only 2 studies reported that universal ticagrelor was cost-effective compared to genotype-guided treatment. All the included articles had good quality. Based on current economic evaluations in the literature, implementing CYP2C19 genotype-guided therapy is a cost-effective approach in guiding the selection of medication in patients with ACS undergoing PCI.

Clinical Utility of CYP2C19 Genotyping to Guide Antiplatelet Therapy in Patients With an Acute Coronary Syndrome or Undergoing Percutaneous Coronary Intervention.

Current guidelines recommend dual antiplatelet therapy-a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin-for patients undergoing percutaneous coronary intervention. Although clopidogrel is the most commonly prescribed P2Y12 inhibitor, it is associated with an increased risk of major adverse cardiovascular events in patients carrying loss-of-function CYP2C19 alleles. In contrast, CYP2C19 genotype does not impact clinical response to prasugrel or ticagrelor. Nevertheless, routine implementation of CYP2C19 genotyping to guide antiplatelet therapy selection has remained controversial because of the lack of large randomized controlled trials evaluating this strategy. Emerging results from registry studies and small clinical trials of CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention offer new insight and contribute to a growing evidence base that supports the clinical utility of a genotyping strategy to personalize antiplatelet therapy selection.

Clinical outcomes of CYP2C19 genotype-guided antiplatelet therapy: existing evidence and future directions.

It is well established that theCYP2C19nonfunctional *2 and *3 polymorphisms impair the bioactivation and antiplatelet effects of clopidogrel, and increase the risk of adverse cardiovascular events following percutaneous coronary intervention. In contrast,CYP2C19genotype does not impact clinical response to prasugrel or ticagrelor. Recent studies have evaluated the impact ofCYP2C19genotype-guided selection of antiplatelet therapy on clinical outcomes and begun to close some of the gaps in knowledge and uncertainty that have impeded widespread clinical implementation of this precision medicine approach. This review will critically evaluate recent data and offer new insight into the potential clinical utility of genotype-guided antiplatelet therapy in the context of current clinical practice guidelines.

CYP2C19 Genotype is an Independent Predictor of Adverse Cardiovascular Outcome in Iraqi Patients on Clopidogrel After Percutaneous Coronary Intervention.

To determine the impact of CYP2C19 genotyping on the occurrence of major adverse cardiovascular events (MACE), in cohort of Iraqi patients on clopidogrel after percutaneous coronary intervention (PCI), a total of 201 Iraqi patients undergoing the latter procedure were enrolled. All enrollees had their CYP2C19 genotyped using polymerase chain reaction and reverse hybridization. Genotyping revealed that CYP2C19 *1, *17, *2, and *8 allele frequencies were, respectively, 0.604, 0.276, 0.117, and 0.0026. After the exclusion of those with 2 loss of function alleles, 186 patients were available for follow-up as long as they were on clopidogrel, or until MACE occurred, which was encountered in 8.6% after a median of 12 months. Among predictors associated with MACE was the carriage of one CYP2C19 loss of function allele {hazard ratio (HR) 8.6 [confidence interval (CI) 3.15-23.4]; P < 0.0005}, hypertension [HR 3.74 (CI 1.06-13.16); P = 0.04], reduced ventricular function [HR 3.88 (1.43-10.54); P = 0.008], and history of previous myocardial infarction [HR 4.9 (CI 1.48-11.33); P = 0.007] by univariate analysis, although only CYP2C19 genotype remained significant by multivariate analysis [HR 11.88 (CI 3.25-43.44); P < 0.0005]. The latter observation favors CYP2C19 genotype-guided antiplatelet therapy and extending the use of alternative antiplatelet drugs to those with single loss of function allele after percutaneous coronary intervention.

Feasibility of clinical pharmacist-led CYP2C19 genotyping for patients receiving non-emergent cardiac catheterization in an integrated health system.

Objective:To assess the feasibility of clinical pharmacist-led CYP2C19 genotype-guided P2Y12 inhibitor antiplatelet drug therapy recommendations to cardiologists in an outpatient cardiology practice.Methods:This was a prospective, open-labeled, single-arm study conducted in an integrated healthcare delivery system between March 1, 2013 and January 23, 2014. Patients requiring non-emergent cardiac catheterization were included. A clinical pharmacist provided interpretation and recommendations from genotyping results. The feasibility of implementing CYP2C19 genotype-guided antiplatelet therapy was assessed by the: 1) percentage of patients approached who consented to CYP2C19 genotyping, 2) percentage of patients with CYP2C19 genotyping results available prior to cardiac catheterization, and 3) percentage of clinical pharmacist CYP2C19 genotype-based antiplatelet recommendations accepted by cardiologists.Results:Of the 43 patients identified for potential recruitment, 22 of these were eligible for study enrollment and 6 (27%) patients consented and received CYP2C19 genotyping. All patients had genotyping results available prior to catheterization and all clinical pharmacists’ antiplatelet therapy recommendations were accepted by the patients’ cardiologists. Three patients had the CYP2C19 wild-type (*1/*1) genotype and the clinical pharmacist recommended clopidogrel therapy. CYP2C19 variant genotypes (i.e., *1/*2, *1/*17, and *2/*17) were found in the other three patients; alternative antiplatelet therapy was recommended for the patient with the *1/*2 genotype, while clopidogrel was recommended for those with *1/*17 and *2/*17 genotypes.Conclusion:A relatively small proportion of patients undergoing non-emergent cardiac catheterization consented to pharmacogenetic testing; however, their cardiologists were receptive to clinical pharmacists conducting such testing and providing corresponding pharmacotherapy recommendations. Future studies should identify patient barriers to pharmacogenetic testing.

Abstract 11802: Clinical Implementation Of CYP2C19-genotype Guided Antiplatelet Therapy Reduces Cardiovascular Events After PCI

Introduction: Clopidogrel is bioactivated by CYP2C19, and the CYP2C19 loss-of-function (LOF) genotype leads to reduced clopidogrel effectiveness after percutaneous coronary intervention (PCI). We examined whether clinical implementation of CYP2C19 genotype-guided antiplatelet therapy (APT) reduces the risk for cardiovascular events after PCI. Methods: CYP2C19 genotyping post-PCI was implemented at UF Health Shands Hospital in July 2012, with alternative APT recommended for LOF allele carriers. Major adverse cardiovascular events (MACE, comprised of cardiovascular death, MI, stroke and stent thrombosis) over the 6 months after PCI were determined via medical record review. MACE was compared between LOF allele carriers switched to alternative APT (LOF-alternative) and both LOF allele carriers who remained on clopidogrel (LOF-clopidogrel) and non-LOF carriers (non-LOF) using Kaplan-Meier method with additional multivariable Cox regression analysis and propensity score adjustment in LOF groups. Results: Of 412 patients (80% with ACS) who underwent PCI and genotyping, 126 (31%) had a LOF allele and 68 (54%) of these received alternative APT (prasugrel n=57, ticagrelor n=8, triple dose clopidogrel n=3). On Kaplan-Meier analysis (Figure), there was a lower incidence of MACE in LOF-alternative vs. LOF-clopidogrel groups and no significant difference between the LOF-alternative and non-LOF groups. On multivariable Cox regression analysis with propensity score adjustment, there was reduced risk of MACE in LOF-alternative vs. LOF-clopidogrel patients (HR 0.09, 95% CI 0.01-0.84, p=0.035). In the LOF-clopidogrel group, the majority of events (83%) occurred within 30 days; all were in patients who presented with an ACS. Conclusion: Changing from clopidogrel to alternative APT after PCI in patients with the CYP2C19 LOF genotype reduces the risk for MACE. These data support CYP2C19 genotyping in patients undergoing PCI, especially in those with ACS.

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

In patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (pPCI), the use of dual antiplatelet therapy is essential to prevent atherothrombotic complications. Therefore, patients are treated with acetylsalicylic acid and clopidogrel, prasugrel, or ticagrelor. Clopidogrel, however, shows a major interindividual variation in antiplatelet effect, which is correlated to an increase in atherothrombotic events in patients with high platelet reactivity. This interindividual variation is partly a result of CYP2C19 genetic variants. Ticagrelor and prasugrel reduce atherothrombotic events but increase bleeding rate and drug costs, as compared with clopidogrel. CYP2C19-based tailoring of antiplatelet therapy might be beneficial to STEMI patients. POPular Genetics (NCT01761786) is a randomized, open-label, multicenter trial involving 2,700 STEMI patients who undergo pPCI. Patients are randomized to CYP2C19 genotyping or routine ticagrelor or prasugrel treatment. In the genotyping group, *1/*1 (wild-type) patients receive clopidogrel, and patients carrying 1 or 2 *2 or *3 loss-of-function alleles receive ticagrelor or prasugrel. The primary net clinical benefit end point is the composite of death, (recurrent) myocardial infarction, definite stent thrombosis, stroke, and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding at 1 year. Primary safety end point is the composite of (PLATO) major and minor bleeding. Cost-effectiveness and quality of life will be assessed by calculating quality-adjusted life-years, net costs per life-year, and per quality-adjusted life-year gained. The POPular Genetics study is the first large-scale trial comparing CYP2C19 genotype-guided antiplatelet therapy to a nontailored strategy in terms of net clinical benefit, safety, and cost-effectiveness.

Personalizing antiplatelet therapy-moving to clinics

Dear Editor, The commentary “Bringing pharmacogenetics to the bedside,” published in this issue by Gupta, focuses on the applications of genetic testing in personalizing antiplatelet therapy. Robust evidence from various studies including genome wide studies has established the genetic influence of CYP2C19 genotypes on the outcome of clopidogrel therapy. Now researchers are attempting to take this from the bench to the bedside. As mentioned by the author in the commentary, cost is a limiting factor for implementing pharmacogenomics in practice. This cost issue was addressed in a model-based cost effectiveness analysis that evaluated the benefit of CYP2C19 genotype-guided antiplatelet therapy over the conventional therapy, irrespective of the genotype [1]. They concluded that genotype-guided antiplatelet therapy is more cost effective, with fewer adverse outcomes. The beginning of personalized medicine in clinical practice can be evidenced from the reports of the prospective proof of concept trial, which introduced point-of-care genetic testing for initiating antiplatelet therapy [2]. This point of care genetic test was validated and gave rapid results within minutes. The test can be effectively done by nurses at the bed side. A more pragmatic approach in the implementation of genotyping in personalized medicine was presented in the Vanderbilt PREDICT project [3]. This multidisciplinary project, with experts from various fields such as medicine, clinical pharmacology and clinical pathology, etc., was designed to incorporate genotyping of CYP2C19 for usage of clopidogrel in individuals undergoing cardiac catheterisation. The project aims at developing electronic medical records of genotyping and evidence based decision-support algorithms and rules in guiding the practitioners for prescribing. Success of this PREDICT project can further lead to incorporation of other drug gene interactions, including warfarin-CYP2C9 and simvastatin-SLCO1B1. Further encouragement is provided by insurance services that decided to reimburse the cost expense spent towards genetic testing [4]. These firms have realised that genetic testing is a cost effective strategy for implementing efficacious drug therapy with minimal side effects. It is reasonable to conclude that medical science has advanced to its best in making the possibility of incorporating pharmacogenomic testing to clinical practice. Hence, the new era of personalized tailored antiplatelet therapy is not very far from our reach.