RESUMEN
BACKGROUND: It is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2Y12 inhibitors. METHODS: We conducted a randomized, open-label, assessor-blinded trial in which patients undergoing primary PCI with stent implantation were assigned in a 1:1 ratio to receive either a P2Y12 inhibitor on the basis of early CYP2C19 genetic testing (genotype-guided group) or standard treatment with either ticagrelor or prasugrel (standard-treatment group) for 12 months. In the genotype-guided group, carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and noncarriers received clopidogrel. The two primary outcomes were net adverse clinical events - defined as death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding defined according to Platelet Inhibition and Patient Outcomes (PLATO) criteria - at 12 months (primary combined outcome; tested for noninferiority, with a noninferiority margin of 2 percentage points for the absolute difference) and PLATO major or minor bleeding at 12 months (primary bleeding outcome). RESULTS: For the primary analysis, 2488 patients were included: 1242 in the genotype-guided group and 1246 in the standard-treatment group. The primary combined outcome occurred in 63 patients (5.1%) in the genotype-guided group and in 73 patients (5.9%) in the standard-treatment group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.0 to 0.7; P<0.001 for noninferiority). The primary bleeding outcome occurred in 122 patients (9.8%) in the genotype-guided group and in 156 patients (12.5%) in the standard-treatment group (hazard ratio, 0.78; 95% CI, 0.61 to 0.98; P = 0.04). CONCLUSIONS: In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy for selection of oral P2Y12 inhibitor therapy was noninferior to standard treatment with ticagrelor or prasugrel at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding. (Funded by the Netherlands Organization for Health Research and Development; POPular Genetics ClinicalTrials.gov number, NCT01761786; Netherlands Trial Register number, NL2872.).
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Clopidogrel/uso terapéutico , Trombosis Coronaria/prevención & control , Citocromo P-450 CYP2C19/genética , Genotipo , Intervención Coronaria Percutánea , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Infarto del Miocardio con Elevación del ST/terapia , Administración Oral , Anciano , Clopidogrel/efectos adversos , Femenino , Hemorragia/inducido químicamente , Humanos , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Clorhidrato de Prasugrel/efectos adversos , Clorhidrato de Prasugrel/uso terapéutico , Medicina de Precisión , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Infarto del Miocardio con Elevación del ST/tratamiento farmacológico , Infarto del Miocardio con Elevación del ST/genética , Método Simple Ciego , Stents , Ticagrelor/efectos adversos , Ticagrelor/uso terapéuticoRESUMEN
BACKGROUND: Glycoprotein IIb/IIIa inhibitors (GPI) are still used in patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (PCI), although discussion about its clinical benefit is ongoing. METHODS: GPI use was analyzed in this subanalysis of the POPular Genetics trial, which randomized STEMI patients to CYP2C19 genotype-guided treatment (clopidogrel or ticagrelor) or standard treatment with ticagrelor/prasugrel. The composite thrombotic endpoint consisted of cardiovascular death, myocardial infarction (MI), definite stent thrombosis, and stroke at 30 days. The combined bleeding endpoint consisted of Platelet Inhibition and Patient Outcomes (PLATO) major and minor bleeding at 30 days. Univariable and multivariable analyses in addition to a propensity score-matched (PSM) analysis were conducted. RESULTS: In total, 2378 patients, of whom 1033 received GPI and 1345 did not, were included. In multivariable analysis, GPI administration was associated with fewer thrombotic events (hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.09-0.55) and MIs (HR 0.24, 95% CI 0.08-0.73). Furthermore, GPI administration was associated with an increase in bleedings (HR 2.02, 95% CI 1.27-3.19), driven by minor bleedings (HR 2.32, 95% CI 1.43-3.76), without a significant difference in major bleedings (HR 0.69, 95% CI 0.19-2.57). In the PSM analysis, no significant association was found. CONCLUSION: In STEMI patients undergoing primary PCI, GPI administration was associated with a reduction in thrombotic events at a cost of an increase in (mostly minor) bleedings in multivariable analysis, while propensity score analysis did not show significant associations.
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Infarto del Miocardio , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST , Humanos , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/terapia , Intervención Coronaria Percutánea/efectos adversos , Inhibidores de Agregación Plaquetaria/efectos adversos , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria , Infarto del Miocardio con Elevación del ST/tratamiento farmacológico , Infarto del Miocardio con Elevación del ST/terapia , Resultado del TratamientoRESUMEN
BACKGROUND: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. METHODS: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. RESULTS: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. CONCLUSIONS: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.
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Enfermedad Coronaria/genética , Factor V/genética , Genotipo , Trombosis/genética , Aterosclerosis , Ensayos Clínicos como Asunto , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/mortalidad , Predisposición Genética a la Enfermedad , Humanos , Polimorfismo de Nucleótido Simple , Medicina de Precisión , Pronóstico , RiesgoRESUMEN
PURPOSE: The POPular Risk Score was developed for the selective intensification of P2Y12 inhibitor treatment with prasugrel instead of clopidogrel in patients undergoing non-urgent percutaneous coronary intervention (PCI) with stent implantation. This score is based on platelet reactivity (VerifyNow P2Y12 assay), CYP2C19 genotyping, and clinical risk factors. Our aim was to determine if the use of this score in clinical practice is associated with a reduction in thrombotic events without increasing bleeding events. METHODS: In a single-center prospective cohort study, patients with a high risk score were treated with prasugrel and patients with a low risk score with clopidogrel. The risk score-guided cohort was compared with a historic cohort of clopidogrel-treated patients. The endpoint consisted of all-cause death, myocardial infarction, stroke, or stent thrombosis during 1 year of follow-up. TIMI major and minor bleeding events were also analyzed. RESULTS: The guided cohort contained 1127 patients, 26.9% of whom were switched to prasugrel according to the POPular Risk Score. The historic cohort contained 893 patients. The incidence of the combined thrombotic endpoint was significantly lower in the guided cohort as compared with the historic cohort (8.4% versus 3.7%, p < 0.001). This strategy was safe with respect to bleeding (4.0% versus 1.3%, p < 0.001, for TIMI major or minor bleeding). Results were comparable after multivariate and propensity score matched and weighted analysis. CONCLUSION: Selective intensification of P2Y12 inhibitor treatment after non-urgent PCI based on the POPular Risk Score is associated with a reduction in thrombotic events without an increase in bleeding events.
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Clopidogrel/uso terapéutico , Citocromo P-450 CYP2C19/genética , Intervención Coronaria Percutánea , Clorhidrato de Prasugrel/uso terapéutico , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Anciano , Clopidogrel/efectos adversos , Citocromo P-450 CYP2C19/metabolismo , Femenino , Genotipo , Hemorragia/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/prevención & control , Pruebas de Función Plaquetaria , Clorhidrato de Prasugrel/efectos adversos , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Riesgo , Accidente Cerebrovascular/prevención & control , Trombosis/prevención & controlRESUMEN
RATIONALE: The P2Y12 receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Platelet inhibition by clopidogrel shows wide interpatient variability, and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. CYP2C19 polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response. STUDY DESIGN: Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics, and cardiovascular outcomes to perform candidate gene and genome-wide studies. RESULTS: In total, 17 study sites from 13 countries participate in the ICPC, contributing individual patient data from 8,829 patients. Available adenosine diphosphate-stimulated platelet function tests included vasodilator-stimulated phosphoprotein assay, light transmittance aggregometry, and the VerifyNow P2Y12 assay. A proof-of-principle analysis based on genotype data provided by each group showed a strong and consistent association between CYP2C19*2 and platelet reactivity (P value=5.1 × 10-40). CONCLUSION: The ICPC aims to identify new loci influencing clopidogrel efficacy by using state-of-the-art genetic approaches in a large cohort of clopidogrel-treated patients to better understand the genetic basis of on-treatment response variability.
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Síndrome Coronario Agudo/tratamiento farmacológico , Clopidogrel/uso terapéutico , Estudio de Asociación del Genoma Completo , Terapia Molecular Dirigida/métodos , Receptores Purinérgicos P2Y12/genética , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/mortalidad , Anciano , Femenino , Estudios de Asociación Genética , Humanos , Internacionalidad , Masculino , Persona de Mediana Edad , Farmacogenética , Pronóstico , Receptores Purinérgicos P2Y12/efectos de los fármacos , Medición de Riesgo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVES: The aim of this study was to determine predictors of very late stent thrombosis (VLST; >1 year after stenting), and to evaluate whether addition of these predictors to the dual antiplatelet therapy (DAPT) score would improve the ability to identify patients at high risk of VLST who might benefit from DAPT. BACKGROUND: VLST is a severe complication of percutaneous coronary intervention (PCI). Extended knowledge about the predictors of VLST is needed to prevent this life-threatening complication. Recent data showed a reduction in VLST after treatment with prolonged DAPT. The DAPT study developed a prediction score to identify patients after PCI who might benefit from prolonged DAPT duration. METHODS: The Dutch stent thrombosis study is a multi-center case-control study. Consecutive patients with definite VLST were included between 2007 and 2014. Baseline characteristics from the index PCI were collected. Independent predictors of VLST were identified and added to the DAPT score to develop the VLST score. RESULTS: In total, 155 VLST cases and 155 matched controls were included. Suboptimal result of stenting, right coronary artery as target vessel, and diffuse coronary artery ectasia were independent predictors of VLST, and added to the DAPT score. The power of the VLST score to identify patients who experienced VLST was increased (AUC, 95%CI; DAPT score: 0.64, 0.57-0.70; VLST score: 0.70, 0.63-0.76, P = 0.010). CONCLUSIONS: Addition of newly identified independent predictors of VLST resulted in a prediction model with a higher ability to identify patients at high risk of VLST who might benefit from prolonged DAPT.
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Efectos Adversos a Largo Plazo/diagnóstico , Infarto del Miocardio/cirugía , Intervención Coronaria Percutánea , Stents/efectos adversos , Trombosis/diagnóstico , Aspirina/uso terapéutico , Estudios de Casos y Controles , Femenino , Hemorragia/inducido químicamente , Hemorragia/epidemiología , Humanos , Efectos Adversos a Largo Plazo/epidemiología , Efectos Adversos a Largo Plazo/etiología , Efectos Adversos a Largo Plazo/prevención & control , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/métodos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Pronóstico , Medición de Riesgo/métodos , Factores de Riesgo , Trombosis/epidemiología , Trombosis/etiología , Trombosis/prevención & control , Ticlopidina/uso terapéuticoRESUMEN
Antiplatelet therapy plays a pivotal role in patients with an ST-segment elevation myocardial infarction (STEMI) to prevent further atherothrombotic events, such as stent thrombosis. Although the risk of stent thrombosis is highest in the first hours after primary percutaneous coronary intervention (pPCI), little is known about when an adequate level of platelet inhibition is achieved following a clopidogrel or ticagrelor loading dose in STEMI patients. Patients presenting with STEMI in whom pPCI was performed and who were loaded with 600 mg clopidogrel or 180 mg ticagrelor were eligible for enrolment in this nonrandomized, open label, single-center study. Platelet reactivity was measured before PCI, 6 and 24 hours after loading dose and after 2, 7, and 14 days, using the VerifyNow P2Y12 assay as well as 20 µmol/L adenosine diphosphate stimulated light transmittance aggregometry (LTA). We analyzed the time until a VerifyNow result of < 236 P2Y12 reaction units or LTA maximum platelet aggregation of < 64.5% was reached. A total of 28 patients were participated in this study. Platelet reactivity dropped below the high platelet reactivity cutoff level after 11.4 (VerifyNow) and 5.7 (LTA) hours in patients who were loaded with clopidogrel, and after 2.4 (VerifyNow) and 3.9 (LTA) hours in patients who were loaded with ticagrelor. Despite the administration of a clopidogrel or ticagrelor loading dose, it still takes multiple hours (2-11) to reach adequate platelet inhibition in STEMI patients. This might indicate the need for additional antiplatelet therapy in the first hours after loading in patients undergoing pPCI with stenting.
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Adenosina/análogos & derivados , Plaquetas/efectos de los fármacos , Intervención Coronaria Percutánea/métodos , Infarto del Miocardio con Elevación del ST/cirugía , Ticlopidina/análogos & derivados , Adenosina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Clopidogrel , Femenino , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Activación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Pruebas de Función Plaquetaria , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Infarto del Miocardio con Elevación del ST/sangre , Trombosis/sangre , Trombosis/prevención & control , Ticagrelor , Ticlopidina/uso terapéutico , Factores de Tiempo , Adulto JovenRESUMEN
OBJECTIVES: The PLATO trial revealed superiority of ticagrelor over clopidogrel for the prevention of atherothrombotic events in patients with acute coronary syndrome. However, adverse events such as bleeding, dyspnea, and bradycardia were frequently reported, potentially leading to excess early ticagrelor discontinuation (ETD), later confirmed in the PEGASUS trial. We here evaluated the incidence and causes for ETD in a real-world patient cohort in a high-volume nonacademic percutaneous coronary intervention center in the Netherlands. METHODS: In a retrospective single-center registry, all patients discharged from the hospital with a new ticagrelor prescription were screened for ETD. Follow-up data were obtained using the hospital electronic patient file records and confirmed by telephone contact with the patient and/or general practitioner, if necessary, to complement the data. RESULTS: Ticagrelor was prescribed in 354 patients between December 2011 and December 2012. The follow-up data were available in 301 patients with a mean follow-up duration of 330 days. ETD or switching to another antiplatelet agent occurred in 73 patients (24.3%), mostly due to dyspnea (11.6%), bleeding (3.7%), or planned major surgery (2.7%). CONCLUSIONS: Almost one quarter of ticagrelor patients were discontinued prematurely or switched to another antiplatelet agent within 1 year, mostly due to dyspnea or bleeding.
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Síndrome Coronario Agudo/tratamiento farmacológico , Adenosina/análogos & derivados , Disnea/epidemiología , Hemorragia/epidemiología , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Adenosina/efectos adversos , Adenosina/uso terapéutico , Anciano , Disnea/inducido químicamente , Femenino , Hemorragia/inducido químicamente , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Países Bajos , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Sistema de Registros , Estudios Retrospectivos , Ticagrelor , Factores de TiempoRESUMEN
RATIONALE: Dual antiplatelet therapy with acetylsalicylic acid in combination with a more potent P2Y12- inhibitor (ticagrelor or prasugrel) is recommended in patients with acute coronary syndrome without ST-segment elevation (NSTE-ACS) to prevent atherothrombotic complications. The evidence on which this recommendation is based shows that ticagrelor and prasugrel reduce atherothrombotic events at the expense of an increase in bleeding events when compared with clopidogrel. However, it remains unclear whether ticagrelor or prasugrel has a better net clinical benefit in elderly patients with NSTE-ACS when compared with clopidogrel. The POPular AGE trial is designed to address the optimal antiplatelet strategy in elderly NSTE-ACS patients. STUDY DESIGN: POPular AGE is a multicenter, open-label, randomized controlled trial that aims to include 1000 patients ≥70years of age with NSTE-ACS. Patients are randomly assigned to receive either clopidogrel or a more potent P2Y12 inhibitor (ticagrelor or prasugrel). The first primary end point is any bleeding event requiring medical intervention. The second primary end point is the net clinical benefit, a composite of all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, "PLATelet inhibition and patient Outcomes" major bleeding, or "PLATelet inhibition and patient Outcomes" minor bleeding. Patients will be followed for 1 year after randomization, and analyses will be performed on the basis of intention to treat. CONCLUSION: The POPular AGE is the first randomized controlled trial that will assess whether the treatment strategy with clopidogrel will result in fewer bleeding events without compromising the net clinical benefit in patients ≥70years of age with NSTE-ACS when compared with a treatment strategy with ticagrelor or prasugrel.
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Síndrome Coronario Agudo/tratamiento farmacológico , Adenosina/análogos & derivados , Clorhidrato de Prasugrel/administración & dosificación , Ticlopidina/análogos & derivados , Adenosina/administración & dosificación , Anciano , Clopidogrel , Femenino , Estudios de Seguimiento , Humanos , Masculino , Inhibidores de Agregación Plaquetaria/administración & dosificación , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Estudios Retrospectivos , Ticagrelor , Ticlopidina/administración & dosificación , Resultado del TratamientoRESUMEN
RATIONALE: 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. STUDY DESIGN: 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. CONCLUSION: 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.
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Hidrocarburo de Aril Hidroxilasas/genética , Electrocardiografía , Técnicas Genéticas , Infarto del Miocardio/genética , Intervención Coronaria Percutánea/métodos , Ticlopidina/análogos & derivados , Adulto , Anciano , Hidrocarburo de Aril Hidroxilasas/metabolismo , Clopidogrel , Citocromo P-450 CYP2C19 , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/terapia , Inhibidores de Agregación Plaquetaria/administración & dosificación , Estudios Prospectivos , Ticlopidina/administración & dosificación , Resultado del Tratamiento , Adulto JovenRESUMEN
Body weight is a predictor of clopidogrel response. However, no prospective studies have compared pharmacodynamic (PD) and pharmacokinetic (PK) data based on body weight. We compared PD and PK effects of clopidogrel 75 mg in low body weight (LBW, <60 kg) and higher body weight (HBW, ≥60 kg) patients with stable coronary artery disease. LBW (n = 34, 56.4 ± 3.7 kg) and HBW (n = 38, 84.7 ± 14.9 kg) aspirin-treated patients received clopidogrel 75 mg for 10-14 days. The area under the concentration-time curve of active metabolite (Clop-AM) calculated through the last quantifiable concentration up to 4 h postdose, AUC(0-tlast), was calculated by noncompartmental methods. Light transmission aggregometry (LTA) (maximum platelet aggregation and inhibition of platelet aggregation to 20 µM adenosine diphosphate (ADP), and residual platelet aggregation to 5 µM ADP), VerifyNow(®) P2Y12 reaction units (PRU), and vasodilator-associated stimulated phosphoprotein phosphorylation platelet reactivity index (VASP-PRI) were performed. Mean AUC(0-tlast) was lower in HBW than LBW patients: 12.8 versus 17.9 ng h/mL. HBW patients had higher platelet reactivity as measured by LTA (all p ≤ 0.01), PRU (207 ± 68 vs. 152 ± 57, p < 0.001), and VASP-PRI (56 ± 18 vs. 39 ± 17, p < 0.001). More HBW patients exhibited high on-treatment platelet reactivity (HPR) using PRU (35 vs. 9%) and VASP-PRI (65 vs. 27%). Body weight correlated with PRU and VASP-PRI (both p < 0.001), and inversely with log transformed AUC(0-tlast) (p < 0.001). In conclusion, HBW patients had lower levels of Clop-AM, and higher platelet reactivity and rates of HPR than LBW subjects, contributing to their suboptimal response to clopidogrel.
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Peso Corporal , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/farmacocinética , Ticlopidina/análogos & derivados , Adolescente , Adulto , Anciano , Plaquetas/metabolismo , Clopidogrel , Femenino , Humanos , Masculino , Persona de Mediana Edad , Agregación Plaquetaria/efectos de los fármacos , Ticlopidina/administración & dosificación , Ticlopidina/farmacocinéticaRESUMEN
Aims: To determine the clinical efficacy, adverse events and side-effect dyspnea of CYP3A4*22 and CYP3A5 expressor status in ticagrelor treated patients. Methods and results: Ticagrelor treated patients from the POPular Genetics randomized controlled trial were genotyped for CYP3A4*22 and CYP3A5*3 alleles. Patients were divided based on their genotype. In total 1,281 patients with ST-segment elevation myocardial infarction (STEMI) were included. CYP3A4*22 carriers (n = 152) versus CYP3A4*22 non-carrier status (n = 1,129) were not found to have a significant correlation with the primary thrombotic endpoint: cardiovascular death, myocardial infarction, definite stent thrombosis and stroke [1.3% vs. 2.5%, adjusted hazard ratio 1.81 (0.43-7.62) p = 0.42], or the primary bleeding endpoint: PLATO major and minor bleeding [13.2% vs. 11.3%, adjusted hazard ratio 0.93 (0.58-1.50) p = 0.77]. Among the CYP3A4*1/*1 patients, CYP3A5 expressors (n = 196) versus non-expressors (n = 926) did not show a significant difference for the primary thrombotic [2.6% vs. 2.5%, adjusted hazard ratio 1.03 (0.39-2.71) p = 0.95], or the primary bleeding endpoint [12.8% vs. 10.9%, adjusted hazard ratio 1.13 (0.73-1.76) p = 0.58]. With respect to dyspnea, no significant difference was observed between CYP3A4*22 carriers versus CYP3A4*22 non-carriers [44.0% vs. 45.0%, odds ratio 1.04 (0.45-2.42) p = 0.93], or in the CYP3A4*1/*1 group, CYP3A5 expressors versus CYP3A5 non-expressors [35.3% vs. 47.8%, odds ratio 0.60 (0.27-1.30) p = 0.20]. Conclusion: In STEMI patients treated with ticagrelor, neither the CYP3A4*22 carriers, nor the CYP3A5 expressor status had a statistical significant effect on thrombotic and bleeding event rates nor on dyspnea. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT01761786.
RESUMEN
INTRODUCTION: The POPular Genetics trial demonstrated that a CYP2C19 genotype-guided P2Y12 inhibitor strategy reduced bleeding rates compared with standard treatment with ticagrelor or prasugrel without increasing thrombotic event rates after primary percutaneous coronary intervention (PCI). OBJECTIVE: In this analysis, we aimed to evaluate the cost effectiveness of a genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel. METHODS: A 1-year decision tree based on the POPular Genetics trial in combination with a lifelong Markov model was developed to compare costs and quality-adjusted life-years (QALYs) between a genotype-guided and a standard P2Y12 inhibitor strategy in patients with myocardial infarction undergoing primary PCI. The cost-effectiveness analysis was conducted from a Dutch healthcare system perspective. Within-trial survival and utility data were combined with lifetime projections to evaluate lifetime cost effectiveness for a cohort of 1000 patients. Costs and utilities were discounted at 4 and 1.5%, respectively, according to Dutch guidelines for health economic studies. Besides deterministic and probabilistic sensitivity analyses, several scenario analyses were also conducted (different time horizons, different discount rates, equal prices for P2Y12 inhibitors, and equal distribution of thrombotic events between the two strategies). RESULTS: Base-case analysis with a hypothetical cohort of 1000 subjects demonstrated 8.98 QALYs gained and 725,550.69 in cost savings for the genotype-guided strategy (dominant). The deterministic and probabilistic sensitivity analysis confirmed the robustness of the model and the cost-effectiveness results. In scenario analyses, the genotype-guided strategy remained dominant. CONCLUSION: In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel resulted in QALYs gained and cost savings. TRIAL REGISTRATION: Clinicaltrials.gov number: NCT01761786, Netherlands trial register number: NL2872.
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Síndrome Coronario Agudo , Infarto del Miocardio , Intervención Coronaria Percutánea , Síndrome Coronario Agudo/terapia , Ensayos Clínicos como Asunto , Clopidogrel , Análisis Costo-Beneficio , Citocromo P-450 CYP2C19/genética , Genotipo , Humanos , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/genética , Inhibidores de Agregación Plaquetaria/uso terapéutico , Clorhidrato de Prasugrel/uso terapéuticoRESUMEN
BACKGROUND: Patients with acute coronary syndrome (ACS) who are carrying CYP2C19 loss-of-function alleles derive less benefit from clopidogrel treatment. Despite this, in elderly patients, clopidogrel might be preferred over more potent P2Y12 inhibitors due to a lower bleeding risk. Whether CYP2C19 genotype-guided antiplatelet treatment in the elderly could be of benefit has not been studied specifically. METHODS: Patients aged 70 years and older with known CYP2C19*2 and *3 genotype were identified from the POPular Genetics and POPular Age trials. Noncarriers of loss-of-function alleles treated with clopidogrel were compared to patients, irrespective of CYP2C19 genotype, treated with ticagrelor and to clopidogrel treated carriers of loss-of-function alleles. We assessed net clinical benefit (all-cause death, myocardial infarction, stroke and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding), atherothrombotic outcomes (cardiovascular death, myocardial infarction, stroke) and bleeding outcomes (PLATO major and minor bleeding). RESULTS: A total of 991 patients were assessed. There was no significant difference in net clinical benefit (17.2% vs. 15.1%, adjusted hazard ratio (adjHR) 1.05, 95% confidence interval (CI) 0.77-1.44), atherothrombotic outcomes (9.7% vs. 9.2%, adjHR 1.00, 95%CI 0.66-1.50), and bleeding outcomes (17.7% vs. 19.8%, adjHR 0.80, 95%CI 0.62-1.12) between clopidogrel in noncarriers of loss-of-function alleles and ticagrelor respectively. CONCLUSION: In ACS patients aged 70 years and older, there was no significant difference in net clinical benefit and atherothrombotic outcomes between noncarriers of a loss-of-function allele treated with clopidogrel and patients treated with ticagrelor. The bleeding rate was numerically; though not statistically significant, lower in patients using clopidogrel.
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Síndrome Coronario Agudo , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/genética , Anciano , Anciano de 80 o más Años , Alelos , Clopidogrel/uso terapéutico , Citocromo P-450 CYP2C19/genética , Genotipo , Humanos , Inhibidores de Agregación Plaquetaria , Ticagrelor , Resultado del TratamientoRESUMEN
[Figure: see text].
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Síndrome Coronario Agudo , Intervención Coronaria Percutánea , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/genética , Clopidogrel/efectos adversos , Citocromo P-450 CYP2C19/genética , Genotipo , Humanos , Intervención Coronaria Percutánea/efectos adversos , Inhibidores de Agregación Plaquetaria/efectos adversos , Clorhidrato de Prasugrel/efectos adversos , Ticagrelor/efectos adversos , Resultado del TratamientoRESUMEN
OBJECTIVES: The aim of this study was to develop a risk score integrating cytochrome P450 2C19 loss-of-function genotypes with clinical risk factors influencing clopidogrel response that would allow the identification with more precision of subjects at risk for high platelet reactivity (HPR) and adverse clinical outcomes. BACKGROUND: Clopidogrel is the most broadly used platelet P2Y12 inhibitor. However, a considerable number of patients achieve inadequate platelet inhibition, with persistent HPR, an established marker of increased thrombotic risk, underscoring the need for tools to help identify these subjects. Although carriers of loss-of-function alleles of the cytochrome P450 2C19 enzyme have reduced clopidogrel metabolism leading to increased rates of HPR and thrombotic complications, this explains only a fraction of the pharmacodynamic response to clopidogrel, and a number of clinical factors have also been shown to have contributing roles. METHODS: Three prospective and independent studies were used to: 1) develop a risk score integrating genetic and clinical factors to identify patients with HPR while on clopidogrel; 2) investigate the external validity of the risk score; and 3) define clinical outcomes associated with the risk score in a cohort of patients with myocardial infarction treated with clopidogrel. RESULTS: A risk score ABCD-GENE (Age, Body Mass Index, Chronic Kidney Disease, Diabetes Mellitus, and Genotyping) was developed incorporating 5 independent predictors of HPR: 4 clinical (age >75 years, body mass index >30 kg/m2, chronic kidney disease [glomerular filtration rate <60 ml/min], and diabetes mellitus) and 1 genetic (cytochrome P450 2C19 loss-of-function alleles). The C-statistics for the score as an integer variable were 0.71 (95% confidence interval [CI]: 0.68 to 0.75) and 0.64 (95% CI: 0.60 to 0.67) in the pharmacodynamic derivation and validation cohorts, respectively. A cutoff score ≥10 was associated with the best sensitivity and specificity to identify HPR status. The C-statistics for the score were 0.67 (95% CI: 0.64 to 0.71) for all-cause death and 0.66 (95% CI: 0.63 to 0.69) for the composite of all-cause death, stroke, or myocardial infarction at 1 year. Using multiple models for adjustment, the ABCD-GENE score consistently and independently correlated with all-cause death, as well as with the composite of all-cause death, stroke, or myocardial infarction, both as a continuous variable and by using the cutoff of ≥10. The score did not predict bleeding. CONCLUSIONS: The ABCD-GENE score is a simple tool to identify patients with HPR on clopidogrel and who are at increased risk for adverse ischemic events, including mortality, following an acute myocardial infarction. In patients with a high ABCD-GENE score, long-term oral P2Y12 inhibitors other than clopidogrel should be considered.
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Reglas de Decisión Clínica , Clopidogrel/uso terapéutico , Trombosis Coronaria/prevención & control , Resistencia a Medicamentos , Infarto del Miocardio/terapia , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria/uso terapéutico , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Factores de Edad , Anciano , Índice de Masa Corporal , Clopidogrel/efectos adversos , Clopidogrel/farmacocinética , Trombosis Coronaria/diagnóstico por imagen , Trombosis Coronaria/etiología , Trombosis Coronaria/mortalidad , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Bases de Datos Factuales , Diabetes Mellitus/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/mortalidad , Obesidad/complicaciones , Obesidad/diagnóstico , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/mortalidad , Variantes Farmacogenómicas , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/farmacocinética , Valor Predictivo de las Pruebas , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Antagonistas del Receptor Purinérgico P2Y/farmacocinética , Ensayos Clínicos Controlados Aleatorios como Asunto , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/diagnóstico , Reproducibilidad de los Resultados , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
This study aims to determine whether genetic variants that influence CYP3A4 expression are associated with platelet reactivity in clopidogrel-treated patients undergoing elective percutaneous coronary intervention (PCI), and to evaluate the influence of statin/fibrate co-medication on these associations. A study cohort was used containing 1124 consecutive elective PCI patients in whom CYP3A4*22 and PPAR-α (G209A and A208G) SNPs were genotyped and the VerifyNow P2Y12 platelet reactivity test was performed. Minor allele frequencies were 0.4% for CYP3A4*22/*22, 6.8% for PPAR-α G209A AA, and 7.0% for PPAR-α A208G GG. CYP3A4*22 was not associated with platelet reactivity. The PPAR-α genetic variants were significantly associated with platelet reactivity (G209A AA: -24.6 PRU [-44.7, -4.6], p = 0.016; A208G GG: -24.6 PRU [-44.3, -4.8], p = 0.015). Validation of these PPAR-α results in two external cohorts, containing 716 and 882 patients, respectively, showed the same direction of effect, although not statistically significant. Subsequently, meta-analysis of all three cohorts showed statistical significance of both variants in statin/fibrate users (p = 0.04 for PPAR-a G209A and p = 0.03 for A208G), with no difference in statin/fibrate non-users. In conclusion, PPAR-α G209A and A208G were associated with lower platelet reactivity in patients undergoing elective PCI who were treated with clopidogrel and statin/fibrate co-medication. Further research is necessary to confirm these findings.
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Anticolesterolemiantes/uso terapéutico , Plaquetas/efectos de los fármacos , Clopidogrel/uso terapéutico , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Citocromo P-450 CYP3A/genética , PPAR alfa/genética , Polimorfismo Genético , Anciano , Estudios de Cohortes , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/patología , Femenino , Humanos , Masculino , Intervención Coronaria Percutánea/métodos , Inhibidores de Agregación Plaquetaria/uso terapéuticoRESUMEN
AIMS: Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial. METHODS AND RESULTS: We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10-54; CES1 G143E, P = 1.3 × 10-16; CYP2C19*17, P = 9.5 × 10-10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10-4; CYP2B6 516 G > T, P = 1.0 × 10-3; CYP2C9*2, P = 1.2 × 10-3; and CYP2C9*3, P = 1.5 × 10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (ß = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (ß = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14-2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35-14.27, P = 0.01) compared to patients who carried six or fewer of these alleles. CONCLUSION: Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.
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Clopidogrel/uso terapéutico , Enfermedad de la Arteria Coronaria/terapia , Técnicas de Apoyo para la Decisión , Intervención Coronaria Percutánea , Variantes Farmacogenómicas , Inhibidores de Agregación Plaquetaria/uso terapéutico , Agregación Plaquetaria/efectos de los fármacos , Polimorfismo de Nucleótido Simple , Anciano , Isquemia Encefálica/mortalidad , Isquemia Encefálica/prevención & control , Clopidogrel/efectos adversos , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/mortalidad , Trombosis Coronaria/mortalidad , Trombosis Coronaria/prevención & control , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/mortalidad , Infarto del Miocardio/prevención & control , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/instrumentación , Intervención Coronaria Percutánea/mortalidad , Agregación Plaquetaria/genética , Inhibidores de Agregación Plaquetaria/efectos adversos , Valor Predictivo de las Pruebas , Medición de Riesgo , Factores de Riesgo , Stents , Accidente Cerebrovascular/mortalidad , Accidente Cerebrovascular/prevención & control , Resultado del TratamientoRESUMEN
Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss-of-function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate-induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e-33). After correction for CYP2C19*2 no other single-nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e-09, 4.53e-08, and 2.60e-10, respectively). CYP2C19*2 is the strongest genetic determinant of on-clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.
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Plaquetas/efectos de los fármacos , Enfermedades Cardiovasculares/prevención & control , Clopidogrel/uso terapéutico , Enfermedad de la Arteria Coronaria/terapia , Citocromo P-450 CYP2C19/genética , Intervención Coronaria Percutánea , Variantes Farmacogenómicas , Inhibidores de Agregación Plaquetaria/uso terapéutico , Polimorfismo de Nucleótido Simple , Anciano , Plaquetas/metabolismo , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/mortalidad , Clopidogrel/efectos adversos , Enfermedad de la Arteria Coronaria/mortalidad , Citocromo P-450 CYP2C19/metabolismo , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/mortalidad , Farmacogenética , Inhibidores de Agregación Plaquetaria/efectos adversos , Medición de Riesgo , Factores de Riesgo , Resultado del TratamientoRESUMEN
Objectives The objective of this registry was to study the safety of prehospital initiation of ticagrelor compared with clopidogrel. Background Ticagrelor has replaced clopidogrel in many hospitals as the routinely used antiplatelet drug in patients with ST-segment elevation myocardial infarction (STEMI). Nevertheless, in the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor was associated with an increase in non-CABG (non-coronary artery bypass grafting)-related major bleeding. Data comparing the safety of ticagrelor and clopidogrel after prehospital initiation of treatment are not available. Methods A retrospective, multicenter registry was performed. Selection criteria were the administration of a prehospital loading dose of ticagrelor or clopidogrel according to the ambulance STEMI treatment protocol and the presentation to a percutaneous coronary intervention-capable hospital in our region between January 2011 and December 2012. Follow-up was performed using the electronic patient files for the time period between the antiplatelet loading dose and hospital discharge. The data were analyzed using a primary bleeding end point (any bleeding) and a secondary thrombotic end point (all-cause mortality, spontaneous myocardial infarction, definite stent thrombosis, stroke, or transient ischemic attack). Results Data of 304 clopidogrel-treated and 309 ticagrelor-treated patients were available for analysis. No significant difference in bleeding rate was observed between both groups, using univariate (17.8 vs. 20.1%; p = 0.47; odds ratio, 1.16 [95% confidence interval, 0.78-1.74]) and multivariate ( p = 0.42) analysis. Also for the secondary thrombotic end point (6.3 vs. 4.9%, p = 0.45), no significant differences were observed. Conclusion In this real-world registry, no significant differences in bleeding or thrombotic event rate were found between ticagrelor and clopidogrel after prehospital initiation of treatment.