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1.
Cells ; 10(5)2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064383

RESUMO

Macrophages comprise a phenotypically and functionally diverse group of hematopoietic cells. Versatile macrophage subsets engage to ensure maintenance of tissue integrity. To perform tissue stress surveillance, macrophages express many different stress-sensing receptors, including purinergic P2X and P2Y receptors that respond to extracellular nucleotides and their sugar derivatives. Activation of G protein-coupled P2Y receptors can be both pro- and anti-inflammatory. Current examples include the observation that P2Y14 receptor promotes STAT1-mediated inflammation in pro-inflammatory M1 macrophages as well as the demonstration that P2Y11 receptor suppresses the secretion of tumor necrosis factor (TNF)-α and concomitantly promotes the release of soluble TNF receptors from anti-inflammatory M2 macrophages. Here, we review macrophage regulation by P2Y purinergic receptors, both in physiological and disease-associated inflammation. Therapeutic targeting of anti-inflammatory P2Y receptor signaling is desirable to attenuate excessive inflammation in infectious diseases such as COVID-19. Conversely, anti-inflammatory P2Y receptor signaling must be suppressed during cancer therapy to preserve its efficacy.


Assuntos
Inflamação/imunologia , Macrófagos/imunologia , Receptores Purinérgicos P2Y/metabolismo , Estresse Fisiológico/imunologia , Animais , COVID-19/sangue , COVID-19/tratamento farmacológico , COVID-19/imunologia , Humanos , Vigilância Imunológica/efeitos dos fármacos , Vigilância Imunológica/imunologia , Inflamação/sangue , Inflamação/tratamento farmacológico , Macrófagos/metabolismo , Camundongos , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Agonistas do Receptor Purinérgico P2Y/farmacologia , Agonistas do Receptor Purinérgico P2Y/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Receptores do Fator de Necrose Tumoral/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/metabolismo
2.
JAMA ; 325(15): 1545-1555, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33877270

RESUMO

Importance: Acute coronary syndrome (ACS) is a major cause of morbidity and mortality in the United States with an annual incidence of approximately 1 million. Dual antiplatelet therapy (DAPT), consisting of aspirin and a P2Y12 inhibitor (clopidogrel, ticagrelor, or prasugrel) reduces cardiovascular event rates after ACS. Observations: In 2016, the updated guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) recommended aspirin plus a P2Y12 inhibitor for at least 12 months for patients with ACS. Since these recommendations were published, new randomized clinical trials have studied different regimens and durations of antiplatelet therapy. Recommendations vary according to the risk of bleeding. If bleeding risk is low, prolonged DAPT may be considered, although the optimal duration of prolonged DAPT beyond 1 year is not well established. If bleeding risk is high, shorter duration (ie, 3-6 months) of DAPT may be reasonable. A high risk of bleeding traditionally is defined as a 1-year risk of serious bleeding (either fatal or associated with a ≥3-g/dL drop in hemoglobin) of at least 4% or a risk of an intracranial hemorrhage of at least 1%. Patients at higher risk are 65 years old or older; have low body weight (BMI <18.5), diabetes, or prior bleeding; or take oral anticoagulants. The newest P2Y12 inhibitors, prasugrel and ticagrelor, are more potent, with high on-treatment residual platelet reactivity of about 3% vs 30% to 40% with clopidogrel and act within 30 minutes compared with 2 hours for clopidogrel. Clinicians should avoid prescribing prasugrel to patients with a history of stroke or transient ischemic attack because of an increased risk of cerebrovascular events (6.5% vs 1.2% with clopidogrel, P = .002) and should avoid prescribing it to patients older than 75 years or who weigh less than 60 kg. The ISAR-REACT-5 trial found that prasugrel reduced rates of death, myocardial infarction, or stroke at 1 year compared with ticagrelor among patients with ACS undergoing percutaneous coronary intervention (9.3% vs 6.9%, P = .006) with no significant difference in bleeding. Recent trials suggested that discontinuing aspirin rather than the P2Y12 inhibitor may be associated with better outcomes. Conclusions and Relevance: Dual antiplatelet therapy reduces rates of cardiovascular events in patients with acute coronary syndrome. Specific combinations and duration of dual antiplatelet therapy should be based on patient characteristics-risk of bleeding myocardial ischemia.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Aspirina/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Administração Oral , Aspirina/farmacologia , Doenças Cardiovasculares/prevenção & controle , Clopidogrel/uso terapêutico , Quimioterapia Combinada , Humanos , Cloridrato de Prasugrel/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Ticagrelor/uso terapêutico
4.
Molecules ; 26(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915807

RESUMO

Clopidogrel is a widely-used antiplatelet drug. It is important for the treatment and prevention of coronary heart disease. Clopidogrel can effectively reduce platelet activity and therefore reduce stent thrombosis. However, some patients still have ischemic events despite taking the clopidogrel due to the alteration in clopidogrel metabolism attributable to various genetic and non-genetic factors. This review aims to summarise the mechanisms and causes of clopidogrel resistance (CR) and potential strategies to overcome it. This review summarised the possible effects of genetic polymorphism on CR among the Asian population, especially CYP2C19 *2 / *3 / *17, where the prevalence rate among Asians was 23.00%, 4.61%, 15.18%, respectively. The review also studied the effects of other factors and appropriate strategies used to overcome CR. Generally, CR among the Asian population was estimated at 17.2-81.6%. Therefore, our overview provides valuable insight into the causes of RC. In conclusion, understanding the prevalence of drug metabolism-related genetic polymorphism, especially CYP2C19 alleles, will enhance clinical understanding of racial differences in drug reactions, contributing to the development of personalised medicine in Asia.


Assuntos
Clopidogrel/farmacologia , Doença das Coronárias/epidemiologia , Doença das Coronárias/genética , Resistência a Medicamentos/genética , Variantes Farmacogenômicos , Inibidores da Agregação Plaquetária/farmacologia , Polimorfismo de Nucleotídeo Único , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Alelos , Ásia/epidemiologia , Grupo com Ancestrais do Continente Asiático/genética , Clopidogrel/uso terapêutico , Doença das Coronárias/tratamento farmacológico , Citocromo P-450 CYP2C19/genética , Gerenciamento Clínico , Interações Medicamentosas , Feminino , Humanos , Masculino , Inibidores da Agregação Plaquetária/uso terapêutico , Vigilância da População , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Medição de Risco , Fatores de Risco
5.
Int J Mol Sci ; 22(6)2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33804754

RESUMO

Lipids play an essential role in platelet functions. It is known that polyunsaturated fatty acids play a role in increasing platelet reactivity and that the prothrombotic phenotype plays a crucial role in the occurrence of major adverse cardiovascular events. The ongoing increase in cardiovascular diseases' incidence emphasizes the importance of research linking lipids and platelet function. In particular, the rebound phenomenon that accompanies discontinuation of clopidogrel in patients receiving dual antiplatelet therapy has been associated with changes in the lipid profile. Our many years of research underline the importance of reduced HDL values for the risk of such a rebound effect and the occurrence of thromboembolic events. Lipids are otherwise a heterogeneous group of molecules, and their signaling molecules are not deposited but formed "on-demand" in the cell. On the other hand, exosomes transmit lipid signals between cells, and the profile of such changes can be monitored by lipidomics. Changes in the lipid profile are organ-specific and may indicate new drug action targets.


Assuntos
Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Metabolismo dos Lipídeos , Lipídeos , Inibidores da Agregação Plaquetária/farmacologia , Animais , Humanos , Lipídeos/química , Lipoproteínas HDL/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/química , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico
6.
J Stroke Cerebrovasc Dis ; 30(5): 105681, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33652345

RESUMO

BACKGROUND: A third to half of recurrent stroke occur while on antiplatelet therapy, but no study has explored factors relating to prognosis of recurrent ischemic stroke. This study aimed to clarify the risk factors to determine the clinical outcome of recurrent ischemic stroke. METHODS: A total of 1,333 consecutive acute ischemic stroke patients (first n = 492, recurrent n = 841) were enrolled. We explored factors influencing the modified Rankin Scales (mRS) at discharge that included platelet aggregability, preceding medicines, and well-known risks of biochemical data using Chi-square test or Fisher's exact probability test. RESULTS: As to preceding medicines, the proportion of patients who were functionally independent (mRS 0-2) at discharge was higher in preceding P2Y12 inhibitor that suppressed ADP- and collagen-induced macro-aggregation of platelet and Xa inhibitor or warfarin in cardioembolic stroke, but lower in P2Y12 inhibitor and Xa inhibitor or warfarin in lacunar stroke compared with no medicine. Regardless of LDL-cholesterol and HA1c, the mRS at discharge ≤ 2 was increased in the third tertile of serum albumin and body mass index (BMI) in atherothrombotic stroke; serum albumin and high-density lipoprotein cholesterol (HDL-C) in lacunar stroke; and serum albumin, HDL-C and BMI in cardioembolic stroke. Logistic regression analysis identified the following independent predictors for clinical outcome: serum albumin, HDL-C, BMI, and preceding Xa inhibitor and P2Y12 inhibitor. CONCLUSION: Regardless of well-known risk factors such as diabetes and high LDL-C, preceding treatment for Xa inhibitor or P2Y12 inhibitor, serum albumin, HDL-C, and BMI were associated with prognosis in recurrent ischemic stroke.


Assuntos
Índice de Massa Corporal , Inibidores do Fator Xa/uso terapêutico , AVC Isquêmico/etiologia , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Albumina Sérica Humana/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , HDL-Colesterol/sangue , Avaliação da Deficiência , Feminino , Estado Funcional , Humanos , AVC Isquêmico/sangue , AVC Isquêmico/diagnóstico , AVC Isquêmico/fisiopatologia , Masculino , Pessoa de Meia-Idade , Limitação da Mobilidade , Prognóstico , Recidiva , Medição de Risco , Fatores de Risco
7.
PLoS One ; 16(1): e0245433, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33439911

RESUMO

BACKGROUND: Intravenous morphine (MO) decreases the effect of all oral platelet P2Y12 receptor inhibitors in vitro and observational reports suggest that its use may be associated with larger infarct size. Yet, there are limited data available about the impact of this interaction on clinical outcomes. We studied the effect of MO on mortality in ST-segment elevation myocardial infarction (STEMI) patients treated with primary PCI using a prospective registry. METHODS: Of the 1255 patients who underwent primary PCI, 397 received MO based on physician's judgment. Clopidogrel was used as P2Y12 receptor antagonist in all cases. Median follow-up time was 7.5 years with 457 deaths. To adjust for confounding, two propensity score-based procedures were performed: 1 to 1 matching (PSM, 728 cases), and inverse probability of treatment weighting (IPTW) retaining data from all patients. Primary outcome measure was time to all-cause death, whereas predischarge left ventricular ejection fraction (LVEF) was used as secondary end point. RESULTS: An adequate balance on baseline covariates was achieved by both methods. We found no difference in survival as the HR (MO/no MO) was 0.98 (95% confidence interval [CI]: 0.76-1.26), p = 0.86 using PSM and 1.01 (95% CI: 0.84-1.23), p = 0.88 with IPTW. Likewise, distributions of LVEFs were similar using either methods: with PSM, median LVEFs were 50.0% (interquartile range [IQR]: 43.0%-55.3%) vs 50.0% (IQR: 42.0%-55.0%) in the no MO and MO groups, respectively (p = 0.76), whereas using IPTW, they were 50.0% (IQR: 42.5%-55.0%) vs 50.0% (IQR: 41.0%-55.0%), respectively (p = 0.86). CONCLUSIONS: Our data suggest that morphine use may have no impact on long-term mortality and on predischarge ejection fraction in STEMI patients treated with primary PCI.


Assuntos
Analgésicos Opioides/uso terapêutico , Morfina/uso terapêutico , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Idoso , Analgésicos Opioides/administração & dosagem , Clopidogrel/administração & dosagem , Clopidogrel/uso terapêutico , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Estudos Prospectivos , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Resultado do Tratamento
8.
Int Heart J ; 62(1): 171-174, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33455983

RESUMO

A 41-year-old woman with chest pain for 6 hours was admitted to our chest pain center, presenting with acute myocardial infarction. Coronary angiography showed acute total occlusion in the proximal left anterior descending artery due to late stent thrombosis. After thrombus aspiration and intracoronary administration of 0.5 mg tirofiban, repeated angiography showed that no obvious residual stenosis remained. The patient underwent drug-coated balloon angioplasty 69 days ago and was then administered dual antiplatelet treatment (aspirin and clopidogrel) uninterruptedly. Genetic testing found that both cytochrome P450 2C19 (CYP2C19) (G681A) and glycoprotein Ia (GPIa) (C807T, G873A) were hybrid mutant types, demonstrating that the patient was possibly resistant to clopidogrel and aspirin simultaneously. Thus, clopidogrel was replaced by ticagrelor and no more cardiovascular adverse events occurred during the 2-year follow-up.


Assuntos
Oclusão Coronária/etiologia , Reestenose Coronária/etiologia , Infarto do Miocárdio/diagnóstico , Doença Aguda , Adulto , Assistência ao Convalescente , Angioplastia Coronária com Balão/métodos , Aspirina/administração & dosagem , Aspirina/uso terapêutico , Clopidogrel/administração & dosagem , Clopidogrel/efeitos adversos , Clopidogrel/uso terapêutico , Angiografia Coronária/métodos , Oclusão Coronária/diagnóstico por imagem , Reestenose Coronária/terapia , Citocromo P-450 CYP2C19/genética , Terapia Antiplaquetária Dupla/efeitos adversos , Terapia Antiplaquetária Dupla/métodos , Feminino , Fibrinolíticos/administração & dosagem , Fibrinolíticos/uso terapêutico , Humanos , Integrina alfa2/genética , Mutação/genética , Infarto do Miocárdio/etiologia , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Stents/efeitos adversos , Trombectomia/métodos , Trombose/terapia , Ticagrelor/administração & dosagem , Ticagrelor/uso terapêutico , Tirofibana/administração & dosagem , Tirofibana/uso terapêutico , Resultado do Tratamento
10.
Am J Emerg Med ; 41: 219-228, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33317866

RESUMO

OBJECTIVE: To explore the effects of morphine on P2Y12 platelet inhibitors in patients with acute myocardial infarction (AMI). METHODS: PubMed, Embase, Cochrane Library, and Web of Science were used to retrieve literature through 11th May 2019. Standardized weighted mean difference (SMD) and relative risk (RR) with 95% confidence intervals (CI), P-value, and I2 value were used to assess the strength of the association in this meta-analysis. Outcomes included platelet reactivity, high residual platelet reactivity (HRPR), ticagrelor maximum concentration (Cmax), ticagrelor area under curve (AUC), death rate, reinfarction rate, stroke, stent thrombosis, thrombolysis in myocardial infarction (TIMI) hemorrhage, dyspnea, emesis, contrast-induced nephropathy, and pulmonary edema. RESULTS: A total of 13 articles were included in this study, containing 5688 patients (morphine group: n = 2014, control group: n = 3674). Results illustrated that the morphine group had a higher platelet reactivity (SMD: 0.834, 95%CI: 0.483-1.186, P < 0.001) and HRPR rate (RR: 1.994, 95%CI: 1.536-2.588, P < 0.001) than the control group, while the Cmax of ticagrelor (WMD: -481.838, 95%CI: -841.242-122.434, P = 0.009) was lower than that of the control group. The death rate of the morphine group was lower than that in the control group (RR: 0.561, 95%CI: 0.337-0.933, P = 0.026). The morphine group had a higher emesis rate than the control group (RR: 4.486, 95%CI: 2.263-8.891, P < 0.001). CONCLUSION: Morphine effectively suppresses the inhibition effect of P2Y12 platelet inhibitors in patients with AMI.


Assuntos
Analgésicos Opioides/farmacologia , Morfina/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Ticagrelor/farmacologia , Analgésicos Opioides/uso terapêutico , Interações Medicamentosas , Humanos , Morfina/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Ticagrelor/uso terapêutico
11.
J Stroke Cerebrovasc Dis ; 30(3): 105547, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33360254

RESUMO

OBJECTIVES: The inhibitory effects of P2Y12 receptor antagonist on PAR1- and PAR4-activating peptide (AP)-induced platelet aggregation have not been fully elucidated. The present study aimed to investigate the inhibitory effects of P2Y12 receptor antagonist on PAR1- and PAR4-AP-induced platelet aggregation using platelet-rich plasma (PRP) from individuals including patients with stroke or transient ischemic attack (TIA). MATERIALS AND METHODS: PRP was given to 10 healthy individuals pretreated in vitro with cangrelor, then stimulated with adenosine diphosphate (ADP), PAR4-AP, or PAR1-AP. Moreover, 20 patients were enrolled from 148 consecutive patients with acute ischemic stroke or TIA admitted to our institute between December 2017 and April 2019. PRP obtained from each patient before and >7 days after initiation of clopidogrel was similarly stimulated with these agonists. Platelet aggregation was measured using an automatic coagulation analyzer in all participants. RESULTS: In healthy individuals, ADP- and PAR4-AP-induced platelet aggregations were significantly inhibited depending on the cangrelor concentration in vitro, while PAR1-AP-induced platelet aggregation was slightly inhibited. In patients with stroke or TIA, clopidogrel inhibited ADP-induced platelet aggregation at all concentrations, and significantly inhibited PAR4-AP-induced platelet aggregation at 50 µmol/L of PAR4-AP (p<0.05), especially in 5 patients who showed high reactivity to PAR4-AP. PAR1-AP-induced platelet aggregation was also slightly inhibited. CONCLUSIONS: We showed significant inhibitory effects on PAR4-AP-induced platelet aggregation by clopidogrel in patients with stroke or TIA who had high reactivity to PAR4-AP.


Assuntos
Plaquetas/efeitos dos fármacos , Clopidogrel/uso terapêutico , Ataque Isquêmico Transitório/tratamento farmacológico , AVC Isquêmico/tratamento farmacológico , Oligopeptídeos/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Testes de Função Plaquetária , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Difosfato de Adenosina/farmacologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Plaquetas/metabolismo , Estudos de Casos e Controles , Clopidogrel/efeitos adversos , Feminino , Humanos , Ataque Isquêmico Transitório/sangue , Ataque Isquêmico Transitório/diagnóstico , AVC Isquêmico/sangue , AVC Isquêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/efeitos adversos , Valor Preditivo dos Testes , Estudos Prospectivos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Resultado do Tratamento
12.
Am J Cardiol ; 134: 1-7, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32933753

RESUMO

Mortality in patients with STEMI-associated cardiogenic shock (CS) is increasing. Whether a comprehensive ST-elevation myocardial infarction (STEMI) protocol (CSP) can improve their care delivery and mortality is unknown. We evaluated the impact of a CSP on incidence and outcomes in patients with STEMI-associated CS. We implemented a 4-step CSP including: (1) Emergency Department catheterization lab activation; (2) STEMI Safe Handoff Checklist; (3) immediate catheterization lab transfer; (4) and radial-first percutaneous coronary intervention (PCI). We studied 1,272 consecutive STEMI patients who underwent PCI and assessed for CS incidence per National Cardiovascular Data Registry definitions within 24-hours of PCI, care delivery, and mortality before (January 1, 2011, to July 14, 2014; n = 723) and after (July 15, 2014, to December 31, 2016; n = 549) CSP implementation. Following CSP implementation, CS incidence was reduced (13.0% vs 7.8%, p = 0.003). Of 137 CS patients, 43 (31.4%) were in the CSP group. CSP patients had greater IABP-Shock II risk scores (1.9 ± 1.8 vs 2.8 ± 2.2, p = 0.014) with otherwise similar hemodynamic and baseline characteristics, cardiac arrest incidence, and mechanical circulatory support use. Administration of guideline-directed medical therapy was similar (89.4% vs 97.7%, p = 0.172) with significant improvements in trans-radial PCI (9.6% vs 44.2%, p < 0.001) and door-to-balloon time (129.0 [89:160] vs 95.0 [81:116] minutes, p = 0.001) in the CSP group, translating to improvements in infarct size (CK-MB 220.9 ± 156.0 vs 151.5 ± 98.5 ng/ml, p = 0.005), ejection fraction (40.8 ± 14.5% vs 46.7 ± 14.6%, p = 0.037), and in-hospital mortality (30.9% vs 14.0%, p = 0.037). In conclusion, CSP implementation was associated with improvements in CS incidence, infarct size, ejection fraction, and in-hospital mortality in patients with STEMI-associated CS. This strategy offers a potential solution to bridging the historically elusive gap in their care.


Assuntos
Anticoagulantes/uso terapêutico , Protocolos Clínicos , Mortalidade Hospitalar , Intervenção Coronária Percutânea/métodos , Inibidores da Agregação Plaquetária/uso terapêutico , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Choque Cardiogênico/terapia , Tempo para o Tratamento/estatística & dados numéricos , Idoso , Aspirina/uso terapêutico , Lista de Checagem , Gerenciamento Clínico , Serviço Hospitalar de Emergência , Oxigenação por Membrana Extracorpórea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Artéria Radial , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Choque Cardiogênico/etiologia , Choque Cardiogênico/mortalidade , Volume Sistólico , Resultado do Tratamento
13.
JAMA ; 324(8): 761-771, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32840598

RESUMO

Importance: After percutaneous coronary intervention (PCI), patients with CYP2C19*2 or *3 loss-of-function (LOF) variants treated with clopidogrel have increased risk of ischemic events. Whether genotype-guided selection of oral P2Y12 inhibitor therapy improves ischemic outcomes is unknown. Objective: To determine the effect of a genotype-guided oral P2Y12 inhibitor strategy on ischemic outcomes in CYP2C19 LOF carriers after PCI. Design, Setting, and Participants: Open-label randomized clinical trial of 5302 patients undergoing PCI for acute coronary syndromes (ACS) or stable coronary artery disease (CAD). Patients were enrolled at 40 centers in the US, Canada, South Korea, and Mexico from May 2013 through October 2018; final date of follow-up was October 2019. Interventions: Patients randomized to the genotype-guided group (n = 2652) underwent point-of-care genotyping. CYP2C19 LOF carriers were prescribed ticagrelor and noncarriers clopidogrel. Patients randomized to the conventional group (n = 2650) were prescribed clopidogrel and underwent genotyping after 12 months. Main Outcomes and Measures: The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia at 12 months. A secondary end point was major or minor bleeding at 12 months. The primary analysis was in patients with CYP2C19 LOF variants, and secondary analysis included all randomized patients. The trial had 85% power to detect a minimum hazard ratio of 0.50. Results: Among 5302 patients randomized (median age, 62 years; 25% women), 82% had ACS and 18% had stable CAD; 94% completed the trial. Of 1849 with CYP2C19 LOF variants, 764 of 903 (85%) assigned to genotype-guided therapy received ticagrelor, and 932 of 946 (99%) assigned to conventional therapy received clopidogrel. The primary end point occurred in 35 of 903 CYP2C19 LOF carriers (4.0%) in the genotype-guided therapy group and 54 of 946 (5.9%) in the conventional therapy group at 12 months (hazard ratio [HR], 0.66 [95% CI, 0.43-1.02]; P = .06). None of the 11 prespecified secondary end points showed significant differences, including major or minor bleeding in CYP2C19 LOF carriers in the genotype-guided group (1.9%) vs the conventional therapy group (1.6%) at 12 months (HR, 1.22 [95% CI, 0.60-2.51]; P = .58). Among all randomized patients, the primary end point occurred in 113 of 2641 (4.4%) in the genotype-guided group and 135 of 2635 (5.3%) in the conventional group (HR, 0.84 [95% CI, 0.65-1.07]; P = .16). Conclusions and Relevance: Among CYP2C19 LOF carriers with ACS and stable CAD undergoing PCI, genotype-guided selection of an oral P2Y12 inhibitor, compared with conventional clopidogrel therapy without point-of-care genotyping, resulted in no statistically significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia based on the prespecified analysis plan and the treatment effect that the study was powered to detect at 12 months. Trial Registration: ClinicalTrials.gov Identifier: NCT01742117.


Assuntos
Clopidogrel/uso terapêutico , Doença da Artéria Coronariana/genética , Inibidores do Citocromo P-450 CYP2C19/uso terapêutico , Citocromo P-450 CYP2C19/genética , Intervenção Coronária Percutânea/efeitos adversos , Medicina de Precisão , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Ticagrelor/uso terapêutico , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/genética , Síndrome Coronariana Aguda/cirurgia , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Clopidogrel/efeitos adversos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/terapia , Inibidores do Citocromo P-450 CYP2C19/efeitos adversos , Feminino , Genótipo , Técnicas de Genotipagem , Hemorragia/induzido quimicamente , Heterozigoto , Humanos , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Testes Imediatos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Ticagrelor/efeitos adversos
14.
Am J Cardiol ; 129: 71-78, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32605717

RESUMO

Controversy persists regarding the advisability of anticoagulation for the early period after biological surgical aortic valve replacement (AVR). We aim to examine the impact of various antithrombotic regimens on outcomes in a large cohort of biological AVR patients. Records of 1,111 consecutive adult patients who underwent surgical biological AVR at our institution between 2013 and 2017 were reviewed. Outcomes included stroke, bleeding, and death at 3 and 12 months. Treatment regimens included (1) no therapy, (2) anticoagulants (warfarin or Factor Xa inhibitors), (2) antiplateles (various), and (4) anticoagulants + antiplatelets. Kaplan-Meier analysis was used to track outcomes, and Cox-proportional hazards regression models were conducted to analyze effects of different therapies on adverse events. At 3 months, thromboembolic events were low and not significantly different between the no therapy group (2.2%) and anticoagulation (2.8%) or anticoagulation + antiplatelet (3.6%) or all groups (3.7%). The antiplatelet group was just significantly lower, at 2.2%. However, this was driven by non-stroke cardiovascular events in patients with coronary artery disease. The incidence of death at 3 months was low and not significantly different between all groups. At 12 months, there were no thromboembolic benefits between groups, but bleeding events were significantly higher in the anticoagulation group (no therapy (1.4%), anticoagulation (8.4%), antiplatelet (4.5%), anticoagulation + antiplatelet (7.9%)). In conclusion, none of the antithrombotic regimens showed benefits in stroke or survival at 3 or 12 months after biological AVR. Anticoagulation increased bleeding events. Routine anticoagulation after biological AVR appears to be unnecessary and potentially harmful.


Assuntos
Anticoagulantes/uso terapêutico , Estenose da Valva Aórtica/cirurgia , Bioprótese , Próteses Valvulares Cardíacas , Hemorragia/epidemiologia , Inibidores da Agregação Plaquetária/uso terapêutico , Acidente Vascular Cerebral/epidemiologia , Tromboembolia/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/anormalidades , Valva Aórtica/cirurgia , Insuficiência da Valva Aórtica/complicações , Insuficiência da Valva Aórtica/cirurgia , Estenose da Valva Aórtica/complicações , Aspirina/uso terapêutico , Fibrilação Atrial/complicações , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/tratamento farmacológico , Inibidores do Fator Xa/uso terapêutico , Feminino , Doenças das Valvas Cardíacas/complicações , Doenças das Valvas Cardíacas/cirurgia , Implante de Prótese de Valva Cardíaca , Hemorragia/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mortalidade , Cuidados Pós-Operatórios , Modelos de Riscos Proporcionais , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Varfarina/uso terapêutico , Adulto Jovem
15.
N Engl J Med ; 383(3): 207-217, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32668111

RESUMO

BACKGROUND: Trials have evaluated the use of clopidogrel and aspirin to prevent stroke after an ischemic stroke or transient ischemic attack (TIA). In a previous trial, ticagrelor was not better than aspirin in preventing vascular events or death after stroke or TIA. The effect of the combination of ticagrelor and aspirin on prevention of stroke has not been well studied. METHODS: We conducted a randomized, placebo-controlled, double-blind trial involving patients who had had a mild-to-moderate acute noncardioembolic ischemic stroke, with a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less (range, 0 to 42, with higher scores indicating more severe stroke), or TIA and who were not undergoing thrombolysis or thrombectomy. The patients were assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive a 30-day regimen of either ticagrelor (180-mg loading dose followed by 90 mg twice daily) plus aspirin (300 to 325 mg on the first day followed by 75 to 100 mg daily) or matching placebo plus aspirin. The primary outcome was a composite of stroke or death within 30 days. Secondary outcomes were first subsequent ischemic stroke and the incidence of disability within 30 days. The primary safety outcome was severe bleeding. RESULTS: A total of 11,016 patients underwent randomization (5523 in the ticagrelor-aspirin group and 5493 in the aspirin group). A primary-outcome event occurred in 303 patients (5.5%) in the ticagrelor-aspirin group and in 362 patients (6.6%) in the aspirin group (hazard ratio, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P = 0.02). Ischemic stroke occurred in 276 patients (5.0%) in the ticagrelor-aspirin group and in 345 patients (6.3%) in the aspirin group (hazard ratio, 0.79; 95% CI, 0.68 to 0.93; P = 0.004). The incidence of disability did not differ significantly between the two groups. Severe bleeding occurred in 28 patients (0.5%) in the ticagrelor-aspirin group and in 7 patients (0.1%) in the aspirin group (P = 0.001). CONCLUSIONS: Among patients with a mild-to-moderate acute noncardioembolic ischemic stroke (NIHSS score ≤5) or TIA who were not undergoing intravenous or endovascular thrombolysis, the risk of the composite of stroke or death within 30 days was lower with ticagrelor-aspirin than with aspirin alone, but the incidence of disability did not differ significantly between the two groups. Severe bleeding was more frequent with ticagrelor. (Funded by AstraZeneca; THALES ClinicalTrial.gov number, NCT03354429.).


Assuntos
Aspirina/uso terapêutico , Ataque Isquêmico Transitório/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Ticagrelor/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Aspirina/efeitos adversos , Avaliação da Deficiência , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemorragia/induzido quimicamente , Humanos , Ataque Isquêmico Transitório/complicações , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Prevenção Secundária , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/prevenção & controle , Ticagrelor/efeitos adversos
16.
Medicine (Baltimore) ; 99(29): e20582, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702814

RESUMO

The morbidity of coronary artery disease (CAD) in the Uygur population of Xinjiang was much higher than the national average. Clopidogrel is the most commonly used medication worldwide in dual antiplatelet therapy for CAD, and the response of clopidogrel is affected by CYP2C19, PON1, and ABCB1 genetic polymorphisms. The distribution of CYP2C19*17, ABCB1, and PON1 genetic polymorphisms in Han and Uygur populations with CAD of Xinjiang has not been investigated.This study aimed to investigate the frequencies of CYP2C19, PON1, and ABCB1 genetic polymorphisms, and to identify the metabolizer phenotype of CYP2C19 in Han and Uygur populations with CAD in Northwestern Xinjiang, China. We identified 602 Han and 527 Uygur patients from 2014 through 2019 and studied genotypes for selected allele polymorphisms using sequencing by hybridization.There were significantly different allele frequencies and genotype frequencies between the 2 ethnic groups in terms of CYP2C19*2, *3, *17, ABCB1 and PON1, (P < .05). For CYP2C19*17, the frequency of TT genotype was 2.5% in Uygur patients, but it was undetectable in Han patients. In both the intermediate and poor metabolizer groups, the genotypes polymorphisms CYP2C19*2, *3, *17 were significantly less common in Uygur patients than in Han patients (P < .001). By contrast, the proportion of ultra-metabolizers as defined by CYP2C19*2, *3, *17 polymorphisms significantly higher in Uygur patients (18.6%) than in Han patients (1.7%, P < .001). The CYP2C19*2 frequency was significantly different between Han patients and Han healthy groups (P < .001), while the CYP2C19*3 frequency was significantly different between Uygur patients and Uygur healthy groups (P < .001).Our study supports the notion of interethnic differences in terms of CYP2C19, PON1, and ABCB1 polymorphisms and CYP2C19 genotype-defined clopidogrel metabolic groups. These finding could provide valuable data and insights into personalized CAD treatment for the Uygur and Han populations in Xinjiang.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/genética , Polimorfismo de Nucleotídeo Único/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Arildialquilfosfatase/genética , China/etnologia , Clopidogrel/uso terapêutico , Comorbidade , Doença da Artéria Coronariana/mortalidade , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Grupos Étnicos/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico
17.
Clin Drug Investig ; 40(9): 799-808, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32661914

RESUMO

BACKGROUND AND OBJECTIVES: Dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) reduces the incidence of thrombotic events but increases the risk of bleeding, which is associated with a substantial and durable risk of death and could offset the benefits of a reduction in thrombotic events. P2Y12 inhibitor monotherapy after short-term DAPT could be an option to reduce the risk of bleeding. We carried out a meta-analysis comparing P2Y12 inhibitor monotherapy after short-term DAPT with standard-term DAPT in patients undergoing PCI. METHODS: We searched the PubMed and EMBASE databases through 11 April 2020. Two authors independently reviewed and selected eligible trials. The DerSimonian-Laird method with the binary random-effects model was used to calculate the relative risk (RR) with 95% confidence interval (CI). RESULTS: Five trials involving 23,762 patients were included in the final analyses; four were open-label trials, while the TWILIGHT trial was double-blinded. Ticagrelor was used in three trials, and the other two trials included several P2Y12 inhibitors. P2Y12 inhibitor monotherapy after short-term DAPT significantly reduced the bleeding events, defined as Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding and Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding, by 39% (RR 0.61, 95% CI 0.38-0.99; p = 0.045) and 46% (RR 0.56, 95% CI 0.42-0.73; p < 0.001), respectively. A significant reduction in cardiovascular death was associated with P2Y12 inhibitor monotherapy after short-term DAPT (RR 0.75, 95% CI 0.58-0.98; p = 0.037; I2 = 0). No significant difference in all-cause mortality, myocardial infarction, stroke, or definite or probable stent thrombosis was observed. CONCLUSIONS: This meta-analysis showed a significantly lowered risk of major bleeding and similar benefits of P2Y12 inhibitor monotherapy after short-term DAPT compared with standard-term DAPT in patients undergoing PCI.


Assuntos
Terapia Antiplaquetária Dupla , Intervenção Coronária Percutânea/métodos , Inibidores da Agregação Plaquetária/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Hemorragia/induzido quimicamente , Humanos , Infarto do Miocárdio/prevenção & controle , Inibidores da Agregação Plaquetária/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem
19.
Cardiovasc Drugs Ther ; 34(5): 677-684, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32572652

RESUMO

PURPOSE: To compare the effect of ticagrelor with clopidogrel in reducing the risk of ischemic cardiovascular events in patients with late or very late stent thrombosis (LST/VLST) after primary percutaneous coronary intervention (PCI). METHODS: A total of 4538 patients with acute coronary syndrome were screened for angiographically determined LST/VLST. Two hundred and forty-one patients were included in the analysis and grouped according to ticagrelor (n = 81) or clopidogrel (n = 160) at discharge. The clinical outcome was major adverse cardiovascular events (MACE) defined as death, myocardial infarction (MI), ischemic stroke, and revascularization during the 1-yr follow-up period. RESULTS: After propensity score matching, 65 pairs were generated. The incidence of MACE was significantly lower in the ticagrelor group compared with the clopidogrel group (9.3% vs. 21.5%, log-rank p = 0.048). However, no difference was observed in event rates of death, MI, ischemic stroke, and revascularization between the ticagrelor group and the clopidogrel group. CONCLUSION: Following successful primary PCI, patients with LST/VLST who received ticagrelor had fewer ischemic cardiovascular events at 1-yr follow-up, compared with those who received clopidogrel.


Assuntos
Síndrome Coronariana Aguda/terapia , Clopidogrel/uso terapêutico , Trombose Coronária/prevenção & controle , Intervenção Coronária Percutânea/instrumentação , Inibidores da Agregação Plaquetária/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Stents , Ticagrelor/uso terapêutico , Síndrome Coronariana Aguda/diagnóstico por imagem , Síndrome Coronariana Aguda/mortalidade , Idoso , Clopidogrel/efeitos adversos , Trombose Coronária/etiologia , Trombose Coronária/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Inibidores da Agregação Plaquetária/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Ticagrelor/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
20.
Lancet ; 395(10235): 1487-1495, 2020 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-32386592

RESUMO

BACKGROUND: Antiplatelet therapy is recommended among patients with established atherosclerosis. We compared monotherapy with a P2Y12 inhibitor versus aspirin for secondary prevention. METHODS: In this systematic review and meta-analysis, all randomised trials comparing P2Y12 inhibitor with aspirin monotherapy for secondary prevention in patients with cerebrovascular, coronary, or peripheral artery disease were evaluated for inclusion. On Dec 18, 2019, we searched PubMed, Embase, BioMedCentral, Google Scholar, and the Cochrane Central Register of Controlled Trials. Additionally, we reviewed references from identified articles and searched abstracts from 2017 to 2019 presented at relevant scientific meetings. Data about year of publication, inclusion and exclusion criteria, sample size, baseline patients' features including the baseline condition determining study inclusion (ie, cerebrovascular, coronary, or peripheral artery disease), P2Y12 inhibitor type and dosage, aspirin dosage, endpoint definitions, effect estimates, follow-up duration, and percentage of patients lost to follow-up were collected. Odds ratios (ORs) and 95% CIs were used as metric of choice for treatment effects with random-effects models. Co-primary endpoints were myocardial infarction and stroke. Key secondary endpoints were all-cause death and vascular death. Heterogeneity was assessed with the I2 index. This study is registered with PROSPERO (CRD42018115037). FINDINGS: A total of nine randomised trials were identified and included in this study, and 42 108 patients randomly allocated to a P2Y12 inhibitor (n=21 043) or aspirin (n=21 065) were included in our analyses. Patients who received a P2Y12 inhibitor had a borderline reduction for the risk of myocardial infarction compared with those who received aspirin (OR 0·81 [95% CI 0·66-0·99]; I2=10·9%). Risks of stroke (OR 0·93 [0·82-1·06]; I2=34·5%), all-cause death (OR 0·98 [0·89-1·08]; I2=0%), and vascular death (OR 0·97 [0·86-1·09]; I2=0%) did not differ between patients who received a P2Y12 inhibitor and those who received aspirin. Similarly, the risk of major bleeding (OR 0·90 [0·74-1·10]; I2=3·9%) did not differ between patients who received a P2Y12 inhibitor and those who received aspirin. The number needed to treat to prevent one myocardial infarction with P2Y12 inhibitor monotherapy was 244 patients. Findings were consistent regardless of the type of P2Y12 inhibitor used. INTERPRETATION: Compared with aspirin monotherapy, P2Y12 inhibitor monotherapy is associated with a risk reduction for myocardial infarction and a comparable risk of stroke in the setting of secondary prevention. The benefit of P2Y12 inhibitor monotherapy is of debatable clinical relevance, in view of the high number needed to treat to prevent a myocardial infarction and the absence of any effect on all-cause and vascular mortality. FUNDING: Italian Ministry of Education.


Assuntos
Aspirina/uso terapêutico , Aterosclerose/tratamento farmacológico , Clopidogrel/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Ticagrelor/uso terapêutico , Ticlopidina/uso terapêutico , Idoso , Aterosclerose/complicações , Transtornos Cerebrovasculares/tratamento farmacológico , Doença das Coronárias/tratamento farmacológico , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/prevenção & controle , Doença Arterial Periférica/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Prevenção Secundária/métodos , Acidente Vascular Cerebral/prevenção & controle
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