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 & controlRESUMEN
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 incidence of acute myocardial infarction is increasing in younger age groups, with differences in treatment and outcomes based on gender. ST-elevation myocardial infarction (STEMI) in young adults, however, is incompletely understood as most of the current studies were performed in homogenous populations, did not focus on STEMI, and lack direct comparisons with older adults. We performed a retrospective observational study using the Statewide Planning And Research Cooperative System for all admissions in New York State with a principal diagnosis of STEMI from 2011 to 2018. There were 58,083 STEMIs with the majority being male (68.2%) and non-Hispanic White (64.8%), with an average age of 63.9 ± 13.9 years. Of these, 8,494 (14.6%) occurred in patients aged <50 years. The proportion of STEMIs in women increased with age, from 19.2% in the <50-year-old age group to 48.9% in the ≥70-year-old age group. Young adults with STEMI had greater prevalence of obesity, current tobacco use, other substance use, and major psychiatric disorders, were more likely to receive revascularization, and had lower 1-year mortality than older age groups. Revascularization was associated with at least a 3 times lower odds ratio of 1-year mortality in all age groups. In conclusion, young adults with STEMI had a unique set of risk factors and co-morbidities and were more likely to undergo revascularization than older age groups. In all age groups, female gender was associated with a higher burden of co-morbidities, decreased use of revascularization, and increased 1-year mortality.
Asunto(s)
Revascularización Miocárdica , Infarto del Miocardio con Elevación del ST , Humanos , Masculino , Femenino , Infarto del Miocardio con Elevación del ST/epidemiología , Infarto del Miocardio con Elevación del ST/cirugía , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Anciano , Revascularización Miocárdica/estadística & datos numéricos , Factores de Edad , New York/epidemiología , Adulto , IncidenciaRESUMEN
Atherosclerosis is rare in internal thoracic arteries (ITA) even in patients with severe atherosclerotic coronary artery (ACA) disease. To explore cellular differences, ITA SMC from 3 distinct donors and ACA SMC from 3 distinct donors were grown to sub-confluence and growth arrested for 48 h. Proliferation and thrombospondin-1 (TSP1) production were determined using standard techniques. ITA SMC were larger, grew more slowly and survived more passages than ACA SMC. ACA SMC had a more pronounced proliferative response to 10% serum than ITA SMC. Both ACA SMC and ITA SMC proliferated in response to exogenous TSP1 (12.5 µg/ml and 25 µg/ml) and platelet derived growth factor-BB (PDGF-BB; 20 ng/ml) but TSP1- and PDGF-BB-induced proliferation were partially inhibited by anti-TSP1 antibody A4.1, microRNA-21(miR-21)-3p inhibitors and miR-21-5p inhibitors in each of the 3 ACA SMC lines, but not in any of the ITA SMC lines. PDGF-BB stimulated TSP1 production in ACA SMC but not in ITA SMC but there was no increase in TSP1 levels in conditioned media in either SMC type. In summary, there are significant differences in morphology, proliferative capacity and in responses to TSP1 and PDGF-BB in SMC derived from ITA compared to SMC derived from ACA.
Asunto(s)
Becaplermina , Proliferación Celular , Vasos Coronarios , Miocitos del Músculo Liso , Trombospondina 1 , Becaplermina/metabolismo , Trombospondina 1/metabolismo , Trombospondina 1/genética , Humanos , Proliferación Celular/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Vasos Coronarios/efectos de los fármacos , MicroARNs/genética , MicroARNs/metabolismo , Arterias Mamarias/metabolismo , Arterias Mamarias/efectos de los fármacos , Enfermedad de la Arteria Coronaria/metabolismo , Enfermedad de la Arteria Coronaria/patología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Células Cultivadas , MasculinoRESUMEN
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 TratamientoRESUMEN
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.