RESUMEN

The clinical efficacy and safety of antiplatelet agents vary among patients. Consequently, some patients are at increased risk of recurrent ischemic events during treatment. This interindividual variability can be a result of genetic variants in enzymes that play a role in drug metabolism. The field of pharmacogenomics explores the influence of these genetic variants on an individual's drug response. Tailoring antiplatelet treatment based on genetic variants can potentially result in optimized dosing or a change in drug selection. Most evidence supports guiding therapy based on the CYP2C19 allelic variants in patients with an indication for dual antiplatelet therapy. In ticagrelor-treated or prasugrel-treated patients, a genotype-guided de-escalation strategy can reduce bleeding risk, whereas in patients treated with clopidogrel, an escalation strategy may prevent ischemic events. Although the clinical results are promising, few hospitals have implemented these strategies. New results, technological advancements, and growing experience may potentially overcome current barriers for implementation in the future.

Asunto(s)

Genotipo , Inhibidores de Agregación Plaquetaria , Humanos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de Agregación Plaquetaria/administración & dosificación , Citocromo P-450 CYP2C19/genética , Farmacogenética/métodos , Clorhidrato de Prasugrel/uso terapéutico , Clorhidrato de Prasugrel/administración & dosificación

RESUMEN

The CYP2C19 enzyme metabolizes clopidogrel, a prodrug, to its active form. Approximately 30% of individuals inherit a loss-of-function (LoF) polymorphism in the CYP2C19 gene, leading to reduced formation of the active clopidogrel metabolite. Reduced clopidogrel effectiveness has been well documented in patients with an LoF allele following an acute coronary syndrome or percutaneous coronary intervention. Prasugrel or ticagrelor is recommended in those with an LoF allele as neither is affected by CYP2C19 genotype. Although data demonstrate improved outcomes with a CYP2C19-guided approach to P2Y12 inhibitor selection, genotyping has not yet been widely adopted in clinical practice.

Asunto(s)

Citocromo P-450 CYP2C19 , Antagonistas del Receptor Purinérgico P2Y , Humanos , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Citocromo P-450 CYP2C19/genética , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/genética , Clopidogrel/uso terapéutico , Intervención Coronaria Percutánea/métodos , Genotipo , Ticagrelor/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Clorhidrato de Prasugrel/uso terapéutico , Polimorfismo Genético

RESUMEN

Warfarin dose requirements are highly variable due to clinical and genetic factors. While genetic variants influencing warfarin dose have been identified in European and East Asian populations, more work is needed to identify African-specific genetic variants to help optimize warfarin dosing. We performed genome-wide association studies (GWAS) in four African cohorts from Uganda, South Africa, and Zimbabwe, totalling 989 warfarin-treated participants who reached stable dose and had international normalized ratios within therapeutic ranges. We also included two African American cohorts recruited by the International Warfarin Pharmacogenetics Consortium (n=316) and the University of Alabama at Birmingham (n=199). Following the GWAS, we performed standard error-weighted meta-analyses and then conducted stepwise conditional analyses to account for known loci (the CYP2C cluster SNP rs12777823 and CYP2C9 in chromosome 10; VKORC1 in chromosome 16). The genome-wide significance threshold was set at P<5×10-8. The meta-analysis, comprising 1,504 participants identified 242 significant SNPs across three genomic loci, with 99.6% of these located within known loci on chromosomes 10 (top SNP: rs58800757, P=4.27×10-13) and 16 (top SNP: rs9925964, P=9.97×10-16). Adjustment for the VKORC1 SNP -1639G>A revealed an additional locus on chromosome 2 (top SNPs rs116057875/rs115254730/rs115240773, P=3.64×10-8), implicating the MALL gene, that could indirectly influence warfarin response through interactions with caveolin-1. In conclusion, our meta-analysis of six cohorts of warfarin-treated patients of African ancestry reaffirmed the importance of CYP2C9 and VKORC1 in influencing warfarin dose requirements. We also identified a new locus (MALL), that still requires direct evidence of biological plausibility.

RESUMEN

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) is indicated after percutaneous coronary intervention (PCI) to reduce the risk of atherothrombotic events. Approximately 30% of the US population has a CYP2C19 no-function allele that reduces the effectiveness of clopidogrel, but not prasugrel or ticagrelor, after PCI. We have shown improved outcomes with the integration of CYP2C19 genotyping into clinical care to guide the selection of prasugrel or ticagrelor in CYP2C19 no-function allele carriers. However, the influence of patient-specific demographic, clinical, and other genetic factors on outcomes with genotype-guided DAPT has not been defined. In addition, the impact of genotype-guided de-escalation from prasugrel or ticagrelor to clopidogrel in patients without a CYP2C19 no-function allele has not been investigated in a diverse, real-world clinical setting. The Precision Antiplatelet Therapy after Percutaneous Coronary Intervention (Precision PCI) Registry is a multicenter US registry of patients who underwent PCI and clinical CYP2C19 testing. The registry is enrolling a diverse population, assessing atherothrombotic and bleeding events over 12 months, collecting DNA samples, and conducting platelet function testing in a subset of patients. The registry aims to define the influence of African ancestry and other patient-specific factors on clinical outcomes with CYP2C19-guided DAPT, evaluate the safety and effectiveness of CYP2C19-guided DAPT de-escalation following PCI in a real-world setting, and identify additional genetic influences of clopidogrel response after PCI, with the ultimate goal of establishing optimal strategies for individualized antiplatelet therapy that improves outcomes in a diverse, real-world population.

Asunto(s)

Clopidogrel , Citocromo P-450 CYP2C19 , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria , Clorhidrato de Prasugrel , Medicina de Precisión , Sistema de Registros , Ticagrelor , Humanos , Intervención Coronaria Percutánea/efectos adversos , Citocromo P-450 CYP2C19/genética , Medicina de Precisión/métodos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/efectos adversos , Clopidogrel/administración & dosificación , Clopidogrel/efectos adversos , Ticagrelor/administración & dosificación , Ticagrelor/uso terapéutico , Clorhidrato de Prasugrel/administración & dosificación , Clorhidrato de Prasugrel/uso terapéutico , Clorhidrato de Prasugrel/efectos adversos , Terapia Antiplaquetaria Doble/métodos , Aspirina/administración & dosificación , Aspirina/efectos adversos , Aspirina/uso terapéutico , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Hemorragia/inducido químicamente , Hemorragia/prevención & control

RESUMEN

Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment.

Asunto(s)

Analgésicos Opioides , Dolor Crónico , Citocromo P-450 CYP2D6 , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Analgésicos Opioides/uso terapéutico , Analgésicos Opioides/efectos adversos , Dolor Crónico/tratamiento farmacológico , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Manejo del Dolor/métodos , Dimensión del Dolor , Pruebas de Farmacogenómica , Medicina de Precisión/métodos

RESUMEN

This prospective ex vivo and in vitro pharmacodynamic (PD)/pharmacokinetic investigation was conducted in patients with diabetes mellitus with (n = 31) and without chronic kidney disease (n = 30). PD assessments included platelet reactivity index, maximum platelet aggregation, and P2Y12 reaction units. Ex vivo pharmacokinetic assessments included plasma levels of clopidogrel and its active metabolite. In vitro PD assessments were conducted on baseline samples incubated with escalating concentrations of clopidogrel and its active metabolite. Among patients with diabetes mellitus treated with clopidogrel, impaired renal function was associated with increased maximum platelet aggregation. This finding could be attributed partially to upregulation of the P2Y12 activity without differences in drug absorption or metabolism. (Impact of Chronic Kidney Disease on Clopidogrel Effects in Diabetes Mellitus; NCT03774394).

RESUMEN

The ABCD-GENE score was developed to predict poor response to clopidogrel and includes Age, Body mass index, Chronic kidney disease (CKD; estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2), Diabetes, and CYP2C19 GENE variants; a score ≥ 10 is predictive of reduced clopidogrel effectiveness after percutaneous coronary intervention (PCI). Estimation of GFR without a race variable via the CKD-EPI Scr 2021 equation is now recommended. We examined the impact of using the CKD-EPI Scr 2021 vs. 2009 equation on the ABCD-GENE score for post-PCI patients. A total of 4335 adult patients (n = 925 Black) who underwent PCI and CYP2C19 genotyping were included, with GFR estimated for each patient via the CKD-EPI Scr 2021 and CKD-EPI 2009 equations. The ABCD-GENE score, calculated based on each GFR estimation, was compared. With the CKD-EPI Scr 2021 vs. 2009 equation, median (IQR) eGFR was lower (74 [55-94] vs. 81 [60-103] mL/min/1.73 m2, P < 0.001), and CKD prevalence was higher (31% vs. 25%, P < 0.001) among Black patients, whereas eGFR was higher (85 [65-99] vs. 80 [61-94] mL/min/1.73m2, P < 0.001), and CKD prevalence was lower (20% vs. 24%, P < 0.001) in non-Black patients. This led to 12 (1%) Black patients being reclassified from low to high risk of poor clopidogrel response and 30 (1%) non-Black patients being recategorized from high to low risk (P < 0.001 for both comparisons). Removal of the race variable from GFR estimation significantly impacted the prediction of clopidogrel effectiveness via the ABCD-GENE score.

RESUMEN

The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations for a minimum set of variant alleles (tier 1) and an extended list of variant alleles (tier 2) that will aid clinical laboratories when designing assays for PGx testing. The Association for Molecular Pathology PGx Working Group considered the functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, and other technical considerations for PGx testing when developing these recommendations. The goal of this Working Group is to promote standardization of PGx testing across clinical laboratories. This document will focus on clinical DPYD PGx testing that may be applied to all dihydropyrimidine dehydrogenase-related medications. These recommendations are not to be interpreted as prescriptive but to provide a reference guide.

Asunto(s)

Dihidrouracilo Deshidrogenasa (NADP) , Farmacogenética , Medicina de Precisión , Humanos , Dihidrouracilo Deshidrogenasa (NADP)/genética , Farmacogenética/métodos , Medicina de Precisión/métodos , Medicina de Precisión/normas , Genotipo , Bases del Conocimiento , Consenso , Pruebas de Farmacogenómica/métodos , Pruebas de Farmacogenómica/normas , Alelos , Técnicas de Genotipaje/métodos

RESUMEN

There is significant variability in the efficacy and safety of oral P2Y12 inhibitors, which are used to prevent ischemic outcomes in common diseases such as coronary and peripheral arterial disease and stroke. Clopidogrel, a prodrug, is the most used oral P2Y12 inhibitor and is activated primarily after being metabolized by a highly polymorphic hepatic cytochrome CYP2C219 enzyme. Loss-of-function genetic variants in CYP2C219 are common, can result in decreased active metabolite levels and increased on-treatment platelet aggregation, and are associated with increased ischemic events on clopidogrel therapy. Such patients can be identified by CYP2C19 genetic testing and can be treated with alternative therapy. Conversely, universal use of potent oral P2Y12 inhibitors such as ticagrelor or prasugrel, which are not dependent on CYP2C19 for activation, has been recommended but can result in increased bleeding. Recent clinical trials and meta-analyses have demonstrated that a precision medicine approach in which loss-of-function carriers are prescribed ticagrelor or prasugrel and noncarriers are prescribed clopidogrel results in reducing ischemic events without increasing bleeding risk. The evidence to date supports CYP2C19 genetic testing before oral P2Y12 inhibitors are prescribed in patients with acute coronary syndromes or percutaneous coronary intervention. Clinical implementation of such genetic testing will depend on among multiple factors: rapid availability of results or adoption of the concept of performing preemptive genetic testing, provision of easy-to-understand results with therapeutic recommendations, and seamless integration in the electronic health record.

Asunto(s)

Citocromo P-450 CYP2C19 , Antagonistas del Receptor Purinérgico P2Y , Humanos , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Administración Oral , American Heart Association , Estados Unidos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Clopidogrel/uso terapéutico , Pruebas Genéticas/métodos , Clorhidrato de Prasugrel/uso terapéutico , Pruebas de Farmacogenómica , Ticagrelor/uso terapéutico

RESUMEN

BACKGROUND: Cytochrome P450 2C19 (CYP2C19) intermediate and poor metabolizer patients exhibit diminished clopidogrel clinical effectiveness after percutaneous coronary intervention (PCI). However, outcome studies to date have lacked racial diversity. Thus, the impact of CYP2C19 genotype on cardiovascular outcomes in patients treated with clopidogrel who identify as Black or African American remains unclear. METHODS AND RESULTS: Adults among 5 institutions who self-identified as Black or African American, underwent PCI and clinical CYP2C19 genotyping, and were treated with clopidogrel were included. Data were abstracted from health records. Major atherothrombotic (composite of death, myocardial infarction, ischemic stroke, stent thrombosis, or revascularization for unstable angina) and bleeding event rates within 1 year after PCI were compared across CYP2C19 metabolizer groups using multivariable Cox regression adjusted for potential confounders and baseline variables meeting a threshold of P<0.10. The population included 567 Black patients treated with clopidogrel (median age, 62 years; 46% women; 70% with an acute coronary syndrome indication for PCI). Major atherothrombotic events rates were significantly higher among clopidogrel-treated intermediate and poor metabolizers (24 of 125 [19.2%]) versus patients treated with clopidogrel without a no function allele (43 of 442 [9.7%]; 35.1 versus 15.9 events per 100 person-years; adjusted hazard ratio, 2.00 [95% CI, 1.20-3.33], P=0.008). Bleeding event rates were low overall (23 of 567 [4.1%]) and did not differ among the metabolizer groups. CONCLUSIONS: Black patients with CYP2C19 intermediate and poor metabolizer phenotypes who are treated with clopidogrel exhibit increased risk of adverse cardiovascular outcomes after PCI in a real-world clinical setting. Bleeding outcomes should be interpreted cautiously. Prospective studies are needed to determine whether genotype-guided use of prasugrel or ticagrelor in intermediate and poor metabolizers improves outcomes in Black patients undergoing PCI.

Asunto(s)

Negro o Afroamericano , Clopidogrel , Citocromo P-450 CYP2C19 , Hemorragia , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/etnología , Síndrome Coronario Agudo/terapia , Negro o Afroamericano/genética , Clopidogrel/efectos adversos , Clopidogrel/uso terapéutico , Enfermedad de la Arteria Coronaria/etnología , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/terapia , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Genotipo , Hemorragia/inducido químicamente , Hemorragia/genética , Variantes Farmacogenómicas , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Resultado del Tratamiento

RESUMEN

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.

Asunto(s)

Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6 , Depresión , Pruebas de Farmacogenómica , Inhibidores Selectivos de la Recaptación de Serotonina , Adulto , Femenino , Humanos , Masculino , Antidepresivos/uso terapéutico , Antidepresivos/administración & dosificación , Antidepresivos/efectos adversos , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Depresión/tratamiento farmacológico , Depresión/genética , Depresión/diagnóstico , Variantes Farmacogenómicas , Ensayos Clínicos Pragmáticos como Asunto , Estudios Prospectivos , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico

RESUMEN

The ability of freely available in silico tools to predict the effect of non-synonymous single nucleotide polymorphisms (nsSNPs) in pharmacogenes on protein function is not well defined. We assessed the performance of seven sequence-based (SIFT, PolyPhen2, mutation accessor, FATHMM, PhD-SNP, MutPred2, and SNPs & Go) and five structure-based (mCSM, SDM, DDGun, CupSat, and MAESTROweb) tools in predicting the impact of 118 nsSNPs in the CYP2C19, CYP2C9, CYP2B6, CYP2D6, and DPYD genes with known function (24 normal, one increased, 42 decreased, and 51 no-function). Sequence-based tools had a higher median (IQR) positive predictive value (89% [89-94%] vs. 12% [10-15%], P < 0.001) and lower negative predictive value (30% [24-34%] vs. 90% [80-93%], P < 0.001) than structure-based tools. Accuracy did not significantly differ between sequence-based (59% [37-67%]) and structure-based (34% [23-44%]) tools (P = 0.070). Notably, the no-function CYP2C9*3 allele and decreased function CYP2C9*8 allele were predicted incorrectly as tolerated by 100% of sequenced-based tools and as stabilizing by 60% and 20% of structure-based tools, respectively. As a case study, we performed mutational analysis for the CYP2C9*1, *3 (I359L), and *8 (R150H) proteins through molecular dynamic (MD) simulations using S-warfarin as the substrate. The I359L variant increased the distance of the major metabolic site of S-warfarin to the oxy-ferryl center of CYP2C9, and I359L and R150H caused shifts in the conformation of S-warfarin to a position less favorable for metabolism. These data suggest that MD simulations may better capture the impact of nsSNPs in pharmacogenes than other tools.

RESUMEN

The University of Florida Health Precision Medicine Program plays a crucial role in delivering pharmacogenomics (PGx) result notes to providers who request PGx testing. Despite this, there is currently a lack of a formal assessment of provider needs and established best practice design principles to guide the ongoing development of PGx result notes. This study aims to enhance the content and format of the PGx consult note at UF Health by incorporating valuable feedback from healthcare providers. Through in-depth user sessions involving 11 participants, we evaluated the usability of our consult note template. While overall satisfaction with the content was noted, specific sections, including those addressing phenoconversion and the medication list, were identified for revision to enhance clarity based on insightful provider feedback.

RESUMEN

Warfarin dosing remains challenging due to substantial inter-individual variability, which can lead to unsafe or ineffective therapy with standard dosing. Model-informed precision dosing (MIPD) can help individualize warfarin dosing, requiring the selection of a suitable model. For models developed from clinical data, the dependence on the study design and population raises questions about generalizability. Quantitative system pharmacology (QSP) models promise better extrapolation abilities; however, their complexity and lack of validation on clinical data raise questions about applicability in MIPD. We have previously derived a mechanistic warfarin/international normalized ratio (INR) model from a blood coagulation QSP model. In this article, we evaluated the predictive performance of the warfarin/INR model in the context of MIPD using an external dataset with INR data from patients starting warfarin treatment. We assessed the accuracy and precision of model predictions, benchmarked against an empirically based reference model. Additionally, we evaluated covariate contributions and assessed the predictive performance separately in the more challenging outpatient data. The warfarin/INR model performed comparably to the reference model across various measures despite not being calibrated with warfarin initiation data. Including CYP2C9 and/or VKORC1 genotypes as covariates improved the prediction quality of the warfarin/INR model, even after assimilating 4 days of INR data. The outpatient INR exhibited higher unexplained variability, and predictions slightly exceeded observed values, suggesting that model adjustments might be necessary when transitioning from an inpatient to an outpatient setting. Overall, this research underscores the potential of QSP-derived models for MIPD, offering a complementary approach to empirical model development.

Asunto(s)

Anticoagulantes , Citocromo P-450 CYP2C9 , Relación Normalizada Internacional , Modelos Biológicos , Warfarina , Warfarina/administración & dosificación , Humanos , Anticoagulantes/administración & dosificación , Femenino , Masculino , Persona de Mediana Edad , Citocromo P-450 CYP2C9/genética , Anciano , Vitamina K Epóxido Reductasas/genética , Medicina de Precisión/métodos , Coagulación Sanguínea/efectos de los fármacos , Adulto , Monitoreo de Drogas/métodos

RESUMEN

BACKGROUND: An ABCD-GENE (age, body mass index, chronic kidney disease, diabetes, and CYP2C19 genetic variants) score ≥10 predicts reduced clopidogrel effectiveness, but its association with response to alternative therapy remains unclear. OBJECTIVES: The aim of this study was to evaluate the association between ABCD-GENE score and the effectiveness of clopidogrel vs alternative P2Y12 inhibitor (prasugrel or ticagrelor) therapy after percutaneous coronary intervention (PCI). METHODS: A total of 4,335 patients who underwent PCI, CYP2C19 genotyping, and P2Y12 inhibitor treatment were included. The primary outcome was major atherothrombotic events (MAE) within 1 year after PCI. Cox regression was performed to assess event risk in clopidogrel-treated (reference) vs alternatively treated patients, with stabilized inverse probability weights derived from exposure propensity scores after stratifying by ABCD-GENE score and further by CYP2C19 loss-of-function (LOF) genotype. RESULTS: Among patients with scores <10 (n = 3,200), MAE was not different with alternative therapy vs clopidogrel (weighted HR: 0.89; 95% CI: 0.65-1.22; P = 0.475). The risk for MAE also did not significantly differ by treatment among patients with scores ≥10 (n = 1,135; weighted HR: 0.75; 95% CI: 0.51-1.11; P = 0.155). Among CYP2C19 LOF allele carriers, MAE risk appeared lower with alternative therapy in both the group with scores <10 (weighted HR: 0.50; 95% CI: 0.25-1.01; P = 0.052) and the group with scores ≥10 (weighted HR: 0.48; 95% CI: 0.29-0.80; P = 0.004), while there was no difference in the group with scores <10 and no LOF alleles (weighted HR: 1.03; 95% CI: 0.70-1.51; P = 0.885). CONCLUSIONS: These data support the use of alternative therapy over clopidogrel in CYP2C19 LOF allele carriers after PCI, regardless of ABCD-GENE score, while clopidogrel is as effective as alternative therapy in non-LOF patients with scores <10.

Asunto(s)

Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria , Humanos , Clopidogrel , Citocromo P-450 CYP2C19/genética , Intervención Coronaria Percutánea/efectos adversos , Ticagrelor/uso terapéutico , Resultado del Tratamiento , Genotipo

RESUMEN

Previous findings suggest that medically underserved patients are prescribed medications with pharmacogenetic (PGx) guidelines at a high frequency. Thus, underserved patients may especially benefit from PGx testing, but little evidence exists regarding the effect of testing in this population. This pilot study aimed to generate key feasibility data and explore clinical outcomes of PGx implementation in underserved populations. Black and Latino patients were recruited from an outpatient clinic and underwent PGx testing. Feasibility measures included enrollment metrics and actionable genotype frequencies. The primary clinical outcome was patient medication treatment satisfaction 6 months after testing. Implementation outcomes included the number of healthcare provider encounters and medication changes within the 6-month follow-up. Effectiveness outcomes included medication adherence, patient-perceived test value, and time spent discussing medications with providers. Ninety-nine patients completed the study. Proton-pump inhibitors were the most frequent PGx drug class prescribed at baseline (61%) followed by nonsteroidal anti-inflammatory drugs (36%). Patients with an actionable genotype constituted 96% of the population, whereas 28% had an actionable genotype related to their PGx drug. Patient treatment satisfaction significantly increased over the 6 months after PGx testing. In addition, medication adherence and the number of provider encounters significantly increased over the study period. In a pilot study, preemptive PGx testing was feasible in primary care clinics, improved patient treatment satisfaction and adherence, and increased the number of provider encounters in medically underserved patients. Future clinical trials are warranted to assess the long-term effects of PGx testing in a larger diverse patient population.

Asunto(s)

Pruebas de Farmacogenómica , Poblaciones Vulnerables , Humanos , Proyectos Piloto , Estudios de Factibilidad , Área sin Atención Médica , Satisfacción del Paciente , Farmacogenética

RESUMEN

Introduction: This manuscript reports on a pilot program focused on implementing pharmacogenetic testing within the framework of an employer-sponsored medical plan at University of Florida (UF) Health. The aim was to understand the challenges associated with program implementation and to gather insights into patient attitudes towards PGx testing. Methods: The pilot program adopted a partially preemptive approach, targeting patients on current prescriptions for medications with relevant gene-drug associations. Patients were contacted via phone or through the MyChart system and offered pharmacogenetic testing with no additional direct costs. Results: Of 244 eligible patients, 110 agreed to participate. However, only 61 returned the mailed DNA collection kits. Among these, 89% had at least one potentially actionable genotype-based phenotype. Post-test follow-up revealed that while the majority viewed the process positively, 71% preferred a consultation with a pharmacogenetic specialist for better understanding of their results. Barriers to implementation ranged from fatigue with the healthcare system to a lack of understanding of the pharmacogenetic testing and concerns about privacy and potential misuse of genetic data. Conclusion: The findings underscore the need for clearer patient education on pharmacogenetic results and suggest the importance of the role of pharmacogenetic-trained pharmacists in delivering this education. They also highlight issues with relying on incomplete or inaccurate medication lists in patients' electronic health record. The implementation revealed less obvious challenges, the understanding of which could be beneficial for the success of future preemptive pharmacogenetic implementation programs. The insights from the pilot program served to bridge the information gap between patients, providers, and pharmacogenetic -specialists, with the ultimate goal of improving patient care.

RESUMEN

INTRODUCTION: The CYP2D6 enzyme metabolizes opioids commonly prescribed for cancer-related pain, and CYP2D6 polymorphisms may contribute to variability in opioid response. We evaluated the feasibility of implementing CYP2D6-guided opioid prescribing for patients with cancer and reported pilot outcome data. METHODS: Adult patients from two cancer centers were prospectively enrolled into a hybrid implementation-effectiveness clinical trial and randomized to CYP2D6-genotype-guided opioid selection, with clinical recommendations, or usual care. Implementation metrics, including provider response, medication changes consistent with recommendations, and patient-reported pain and symptom scores at baseline and up to 8 weeks, were assessed. RESULTS: Most (87/114, 76%) patients approached for the study agreed to participate. Of 85 patients randomized, 71% were prescribed oxycodone at baseline. The median (range) time to receive CYP2D6 test results was 10 (3-37) days; 24% of patients had physicians acknowledge genotype results in a clinic note. Among patients with CYP2D6-genotype-guided recommendations to change therapy (n = 11), 18% had a change congruent with recommendations. Among patients who completed baseline and follow-up questionnaires (n = 48), there was no difference in change in mean composite pain score (-1.01 ± 2.1 vs. -0.41 ± 2.5; p = 0.19) or symptom severity at last follow-up (3.96 ± 2.18 vs. 3.47 ± 1.78; p = 0.63) between the usual care arm (n = 26) and genotype-guided arm (n = 22), respectively. CONCLUSION: Our study revealed high acceptance of pharmacogenetic testing as part of a clinical trial among patients with cancer pain. However, provider response to genotype-guided recommendations was low, impacting assessment of pain-related outcomes. Addressing barriers to utility of pharmacogenetics results and clinical recommendations will be critical for implementation success.

Asunto(s)

Dolor en Cáncer , Neoplasias , Adulto , Humanos , Analgésicos Opioides/uso terapéutico , Dolor en Cáncer/tratamiento farmacológico , Dolor en Cáncer/genética , Citocromo P-450 CYP2D6/genética , Pautas de la Práctica en Medicina , Dolor/tratamiento farmacológico , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Neoplasias/genética

RESUMEN

The objective of this study was to characterize clinician response following standardization of pharmacogenetic (PGx) clinical decision support alerts at University of Florida (UF) Health. A retrospective analysis of all PGx alerts that fired at a tertiary academic medical center from August 2020 through May 2022 was performed. Alert acceptance rate was calculated and compared across six gene-drug pairs, patient care setting, and clinician specialty. The disposition of the triggering medication was compared with the alert response and evaluated for congruence. There were a total of 818 alerts included for analysis of alert response, 557 alerts included in acceptance rate calculations, and 392 alerts with sufficient information to assess clinical response. The overall acceptance rate was 63%. The alert response and clinical response were congruent for 47% of alerts. Alert response was influenced by the triggering gene-drug pair, clinician specialty, patient care setting, and specialty of the provider who initially ordered the PGx test. Clinical response was mostly incongruent with alert response. Alert acceptance is influenced by the triggering gene-drug pair, clinician specialty, and care setting. Alert response is not a reliable surrogate marker for clinical action. Any future research into the impact of clinical decision support (CDS) alerts should focus on clinical response rather than alert response. Given the reliance on CDS alerts to enhance uptake of PGx, it is worthwhile to further investigate their impact on prescribing and patient outcomes.

Asunto(s)

Sistemas de Apoyo a Decisiones Clínicas , Sistemas de Entrada de Órdenes Médicas , Humanos , Farmacogenética , Estudios Retrospectivos , Registros Electrónicos de Salud