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1.
Tex Heart Inst J ; 46(3): 203-206, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31708704

RESUMO

The platelet aggregation inhibitor ticagrelor, a P2Y12 receptor antagonist, is widely used after angioplasty in patients with acute coronary syndrome. Clinical trial data have shown that it is well tolerated by most patients. We present the case of a 62-year-old woman whose ticagrelor-related asymptomatic and persistent sinus pauses after angioplasty resolved when ticagrelor was replaced with prasugrel.


Assuntos
Síndrome Coronariana Aguda/cirurgia , Angioplastia Coronária com Balão/métodos , Parada Cardíaca/induzido quimicamente , Complicações Pós-Operatórias , Ticagrelor/efeitos adversos , Síndrome Coronariana Aguda/tratamento farmacológico , Eletrocardiografia , Feminino , Parada Cardíaca/diagnóstico , Humanos , Pessoa de Meia-Idade , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos
2.
Artigo em Alemão | MEDLINE | ID: mdl-31639861

RESUMO

BACKGROUND: Ticagrelor as a P2Y12 receptor antagonist is recommended in patients with acute coronary syndrome without a primary cardiosurgical therapy. Severe relevant side effects, especially anaphylactic reactions, have not yet been described in the current literature. CASE PRESENTATION: We describe the first documented case in the current literature with a severe anaphylaxis after ticagrelor in a 76-year-old male patient with ST-elevation myocardial infarction. The diagnosis seems to be objectivated by the observed time-related life-threatening event after repetitive administration of ticagrelor and the rapid stabilization after adequate anaphylactic treatment. CONCLUSION: This case should raise the awareness that a supposedly safe drug can still cause an anaphylactic shock.


Assuntos
Inibidores da Agregação de Plaquetas , Infarto do Miocárdio com Supradesnível do Segmento ST , Choque , Adenosina , Idoso , Humanos , Masculino , Inibidores da Agregação de Plaquetas/efeitos adversos , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Choque/induzido quimicamente , Ticagrelor/efeitos adversos
3.
N Engl J Med ; 381(17): 1621-1631, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31479209

RESUMO

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.).


Assuntos
Clopidogrel/uso terapêutico , Trombose Coronária/prevenção & controle , Citocromo P-450 CYP2C19/genética , Genótipo , Intervenção Coronária Percutânea , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Administração Oral , Idoso , Clopidogrel/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Cloridrato de Prasugrel/efeitos adversos , Cloridrato de Prasugrel/uso terapêutico , Medicina de Precisão , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/genética , Método Simples-Cego , Stents , Ticagrelor/efeitos adversos , Ticagrelor/uso terapêutico
4.
N Engl J Med ; 381(21): 2032-2042, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31556978

RESUMO

BACKGROUND: Monotherapy with a P2Y12 inhibitor after a minimum period of dual antiplatelet therapy is an emerging approach to reduce the risk of bleeding after percutaneous coronary intervention (PCI). METHODS: In a double-blind trial, we examined the effect of ticagrelor alone as compared with ticagrelor plus aspirin with regard to clinically relevant bleeding among patients who were at high risk for bleeding or an ischemic event and had undergone PCI. After 3 months of treatment with ticagrelor plus aspirin, patients who had not had a major bleeding event or ischemic event continued to take ticagrelor and were randomly assigned to receive aspirin or placebo for 1 year. The primary end point was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. We also evaluated the composite end point of death from any cause, nonfatal myocardial infarction, or nonfatal stroke, using a noninferiority hypothesis with an absolute margin of 1.6 percentage points. RESULTS: We enrolled 9006 patients, and 7119 underwent randomization after 3 months. Between randomization and 1 year, the incidence of the primary end point was 4.0% among patients randomly assigned to receive ticagrelor plus placebo and 7.1% among patients assigned to receive ticagrelor plus aspirin (hazard ratio, 0.56; 95% confidence interval [CI], 0.45 to 0.68; P<0.001). The difference in risk between the groups was similar for BARC type 3 or 5 bleeding (incidence, 1.0% among patients receiving ticagrelor plus placebo and 2.0% among patients receiving ticagrelor plus aspirin; hazard ratio, 0.49; 95% CI, 0.33 to 0.74). The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (difference, -0.06 percentage points; 95% CI, -0.97 to 0.84; hazard ratio, 0.99; 95% CI, 0.78 to 1.25; P<0.001 for noninferiority). CONCLUSIONS: Among high-risk patients who underwent PCI and completed 3 months of dual antiplatelet therapy, ticagrelor monotherapy was associated with a lower incidence of clinically relevant bleeding than ticagrelor plus aspirin, with no higher risk of death, myocardial infarction, or stroke. (Funded by AstraZeneca; TWILIGHT ClinicalTrials.gov number, NCT02270242.).


Assuntos
Aspirina/uso terapêutico , Doença das Coronárias/terapia , Hemorragia/induzido quimicamente , Intervenção Coronária Percutânea , Inibidores da Agregação de Plaquetas/uso terapêutico , Ticagrelor/uso terapêutico , Idoso , Aspirina/efeitos adversos , Doença das Coronárias/tratamento farmacológico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mortalidade , Infarto do Miocárdio/epidemiologia , Inibidores da Agregação de Plaquetas/efeitos adversos , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Ticagrelor/efeitos adversos
5.
N Engl J Med ; 381(16): 1524-1534, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31475799

RESUMO

BACKGROUND: The relative merits of ticagrelor as compared with prasugrel in patients with acute coronary syndromes for whom invasive evaluation is planned are uncertain. METHODS: In this multicenter, randomized, open-label trial, we randomly assigned patients who presented with acute coronary syndromes and for whom invasive evaluation was planned to receive either ticagrelor or prasugrel. The primary end point was the composite of death, myocardial infarction, or stroke at 1 year. A major secondary end point (the safety end point) was bleeding. RESULTS: A total of 4018 patients underwent randomization. A primary end-point event occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and in 137 of 2006 patients (6.9%) in the prasugrel group (hazard ratio, 1.36; 95% confidence interval [CI], 1.09 to 1.70; P = 0.006). The respective incidences of the individual components of the primary end point in the ticagrelor group and the prasugrel group were as follows: death, 4.5% and 3.7%; myocardial infarction, 4.8% and 3.0%; and stroke, 1.1% and 1.0%. Definite or probable stent thrombosis occurred in 1.3% of patients assigned to ticagrelor and 1.0% of patients assigned to prasugrel, and definite stent thrombosis occurred in 1.1% and 0.6%, respectively. Major bleeding (as defined by the Bleeding Academic Research Consortium scale) was observed in 5.4% of patients in the ticagrelor group and in 4.8% of patients in the prasugrel group (hazard ratio, 1.12; 95% CI, 0.83 to 1.51; P = 0.46). CONCLUSIONS: Among patients who presented with acute coronary syndromes with or without ST-segment elevation, the incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel than among those who received ticagrelor, and the incidence of major bleeding was not significantly different between the two groups. (Funded by the German Center for Cardiovascular Research and Deutsches Herzzentrum München; ISAR-REACT 5 ClinicalTrials.gov number, NCT01944800.).


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Cloridrato de Prasugrel/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Ticagrelor/uso terapêutico , Síndrome Coronariana Aguda/mortalidade , Síndrome Coronariana Aguda/terapia , Idoso , Trombose Coronária/epidemiologia , Feminino , Hemorragia/induzido quimicamente , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/prevenção & controle , Intervenção Coronária Percutânea , Inibidores da Agregação de Plaquetas/efeitos adversos , Cloridrato de Prasugrel/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Stents , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Ticagrelor/efeitos adversos
6.
N Engl J Med ; 381(14): 1309-1320, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31475798

RESUMO

BACKGROUND: Patients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin improves outcomes in this population is unclear. METHODS: In this randomized, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria. RESULTS: A total of 19,220 patients underwent randomization. The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P = 0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P = 0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P = 0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02). CONCLUSIONS: In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. (Funded by AstraZeneca; THEMIS ClinicalTrials.gov number, NCT01991795.).


Assuntos
Aspirina/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Ticagrelor/uso terapêutico , Idoso , Aspirina/efeitos adversos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/mortalidade , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Feminino , Seguimentos , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Hemorragia/mortalidade , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/prevenção & controle , Inibidores da Agregação de Plaquetas/efeitos adversos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Ticagrelor/efeitos adversos , Resultado do Tratamento
7.
Vasc Med ; 24(5): 422-430, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31339474

RESUMO

In patients with symptomatic peripheral artery disease (PAD), the impact of chronic kidney disease (CKD) on major adverse cardiovascular events has not been fully evaluated. The Examining Use of Ticagrelor In PAD (EUCLID) trial randomized 13,885 patients with PAD to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. This post hoc analysis compared the incidence of the primary composite endpoint (cardiovascular death, myocardial infarction (MI), or ischemic stroke) in patients with CKD (eGFR < 60 mL/min/1.73 m2) with those without CKD (eGFR ⩾ 60 mL/min/1.73 m2). The primary safety endpoint was thrombolysis in MI (TIMI) major bleeding. A total of 13,483 patients were included; 3332 (25%) had CKD, of whom 237 had stage 4/5 disease. Median follow-up was approximately 30 months. After statistical adjustment, patients with CKD had a higher rate of the primary endpoint compared with those without CKD (6.75 vs 3.72 events/100 patient-years; adjusted hazard ratio (HR) 1.45, 95% CI 1.30-1.63). CKD was not associated with increased risk of hospitalization for acute limb ischemia (ALI) (adjusted HR 0.96, 95% CI 0.69-1.34) or major amputation (adjusted HR 0.92, 95% CI 0.66-1.28). CKD was not associated with a significantly increased risk of major bleeding (adjusted HR 1.21, 95% CI 0.89-1.64), but minor bleeding was significantly increased (adjusted HR 1.51, 95% CI 1.07-2.15). In conclusion, patients with PAD and CKD had higher rates of cardiovascular death, MI, and ischemic stroke, but similar rates of ALI, major amputation, and TIMI major bleeding when compared with patients without CKD. ClinicalTrials.gov Identifier: NCT01732822.


Assuntos
Clopidogrel/administração & dosagem , Taxa de Filtração Glomerular , Isquemia/tratamento farmacológico , Rim/fisiopatologia , Doença Arterial Periférica/tratamento farmacológico , Inibidores da Agregação de Plaquetas/administração & dosagem , Insuficiência Renal Crônica/fisiopatologia , Ticagrelor/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Amputação , Isquemia Encefálica/mortalidade , Isquemia Encefálica/prevenção & controle , Clopidogrel/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Hemorragia/mortalidade , Humanos , Incidência , Isquemia/diagnóstico , Isquemia/mortalidade , Isquemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/prevenção & controle , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/mortalidade , Doença Arterial Periférica/fisiopatologia , Inibidores da Agregação de Plaquetas/efeitos adversos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/mortalidade , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/prevenção & controle , Ticagrelor/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
8.
Clin Adv Hematol Oncol ; 17(4): 234-243, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31188815

RESUMO

BACKGROUND: Sickle cell disease (SCD) is the most common hemoglobinopathy, occurring worldwide, and vaso-occlusive events (VOEs) are its paramount, hallmark clinical manifestation. Evidence exists that platelets play an important role in generating VOEs. OBJECTIVE: To assess the clinical benefits and harms of antiplatelet agents for preventing VOEs in patients with SCD. METHODS: We conducted searches of the Cochrane Central Register of Controlled Trials (CENTRAL; up to 2018, issue 3 of 12), PubMed/MEDLINE (up to April 20, 2018), and the Excerpta Medica database (EMBASE; from 1980 to week 16 of 2018). We also searched the Latin American and Caribbean Health Sciences Literature (LILACS) database, the US Food and Drug Administration (FDA) website, the European Medicines Agency (EMA) website, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and www.ClinicalTrials.gov. We checked the bibliographies of included studies and any relevant systematic reviews. Our systematic review included randomized clinical trials (RCTs) conducted in people who had SCD without VOEs at trial entry. Eligible trials compared a single or combination treatment regimen (with each treatment classified as a conventional or nonconventional antiplatelet agent) with conventional care, placebo, or another regimen. No restrictions were placed on the route of administration, dose, frequency, or duration of treatment. We selected RCTs, assessed the risk for bias, and extracted data in a duplicate and independent fashion. We estimated risk ratios for dichotomous outcomes and mean differences for continuous outcomes. We also subjected our analyses to a random-effects model, and Trial Sequential Analysis (TSA) was used. We used the grading of recommendations, assessment, development, and evaluation (GRADE) approach to assess the overall quality of data for each individual outcome. RESULTS: We identified 5 RCTs (N=747) that met our criteria. Of these, 4 trials were multicenter and multinational. The trials included patients of all ages and assessed prasugrel, ticagrelor, crizanlizumab, and aspirin vs either placebo or no intervention. The most frequent route of administration was oral. The trials were small and carried a high risk for bias, given that pharmaceutical companies sponsored 4 of them. None of the trials reported information on quality of life. No meta-analysis was performed owing to heterogeneity in the ages of the participants and in the interventions. No single trial showed evidence of certainty regarding all-cause mortality. One trial showed uncertainty in comparing prasugrel vs placebo for preventing VOEs in patients younger than 18 years (relative risk [RR], 0.92; 95% CI, 0.80 to 1.06; low quality of evidence). TSA for this outcome suggested that a new trial should be conducted. One trial found a difference in the size effect of uncomplicated VOEs, favoring high-dose crizanlizumab vs placebo (mean difference, -1.50; 95% CI, -2.61 to -0.39; very low quality of evidence). No difference in VOEs was found in studies that compared either ticagrelor in children or prasugrel in adults vs placebo. The overall incidence of harms in any intervention did not differ from that in the control. CONCLUSIONS: The current evidence does not support or reject the use of any antiplatelet agent for preventing VOEs in people with SCD. This conclusion was based on small RCTs that carried a high risk for bias. No conclusive evidence exists regarding relevant clinical outcomes because the evidence is limited and of very low quality.


Assuntos
Anemia Falciforme/complicações , Inibidores da Agregação de Plaquetas/uso terapêutico , Doenças Vasculares/prevenção & controle , Adulto , Anemia Falciforme/fisiopatologia , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Hemorragia/induzido quimicamente , Humanos , Mortalidade , Estudos Multicêntricos como Assunto , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/classificação , Cloridrato de Prasugrel/efeitos adversos , Cloridrato de Prasugrel/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Ticagrelor/efeitos adversos , Ticagrelor/uso terapêutico , Resultado do Tratamento , Doenças Vasculares/etiologia , Doenças Vasculares/fisiopatologia
9.
Cardiovasc Diabetol ; 18(1): 77, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174526

RESUMO

BACKGROUND: Microvascular blood flow (MBF) impairment in patients with lower extremity arterial disease (LEAD) is associated with more severe major adverse limb events (MALE). The contribution of ticagrelor, a P2Y12 antagonist and an adenosine enhancer, on blood viscosity (BV) and BV-dependent MBF in LEAD is unknown. The aim of the trial is to investigate the effects of ticagrelor on BV, and explore the association of BV-dependent MBF in participants with LEAD and type 2 diabetes (T2DM). METHODS: Randomized, double-blind, double-dummy, crossover trial design that compares treatment with aspirin 81 mg/ticagrelor placebo, aspirin 81 mg/ticagrelor 90 mg twice daily and aspirin placebo/ticagrelor 90 mg twice daily on high-shear (300 s-1) and low-shear (5 s-1) BV, and laser Doppler flowmetry (LDF) in the dorsum of the feet of participants with T2DM. RESULTS: We randomized 70 (45% female) participants aged (mean ± SD) 72 ± 9 years. The duration of LEAD was 12.3 ± 10.3 years, and 96.9% reported intermittent claudication symptoms. Use of statins was 93% (high-intensity 43%, moderate intensity 49%), renin-angiotensin-aldosterone system inhibitors (75%) and beta-blockers (61%). Treatment with ticagrelor with or without aspirin reduced high-shear BV by 5%, in both cases, while aspirin monotherapy increased high-shear BV by 3.4% (p < 0.0001). Ticagrelor with or without aspirin reduced low-shear BV by 14.2% and 13.9% respectively, while aspirin monotherapy increased low-shear BV by 9.3% (p < 0.0001). The combination of ticagrelor and aspirin increased MBF in the left foot compared to the other two treatments (p = 0.02), but not in the right foot (p = 0.25). CONCLUSIONS: Ticagrelor should be considered in the treatment of microvascular disease in patients with LEAD and T2DM. Trial registration Registration number: NCT02325466, registration date: December 25, 2014.


Assuntos
Viscosidade Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Extremidade Inferior/irrigação sanguínea , Microcirculação/efeitos dos fármacos , Doença Arterial Periférica/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Ticagrelor/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Velocidade do Fluxo Sanguíneo , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque , Doença Arterial Periférica/sangue , Doença Arterial Periférica/complicações , Doença Arterial Periférica/fisiopatologia , Inibidores da Agregação de Plaquetas/efeitos adversos , Fluxo Sanguíneo Regional , Ticagrelor/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
10.
Minerva Med ; 110(5): 410-418, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31081301

RESUMO

BACKGROUND: Patients with acute coronary syndrome (ACS) and previous cardiovascular disease (CVD) (stroke, peripheral arterial disease [PAD] or coronary artery disease [CAD]) are at high risk of serious events and mortality. Current clinical guidelines recommend new antiplatelet drugs (NADs) for high cardiovascular risk patients with ACS; however, these drugs are underused in different scenarios. METHODS: This study included 1717 ACS patients from 3 tertiary hospitals. Of them, 641 (37.33%) suffered from previous CVD: 149 patients with stroke, 154 patients with PAD and 541 patients with CAD. Bleeding, mortality and major adverse cardiac events (MACE) at 1 year of follow-up after hospital discharge were analyzed. RESULTS: NADs administration during hospital stay and at discharge was less frequent in patients with previous CVDs (P<0.001, for both). Cox analysis in this cohort of patients showed that clopidogrel prescription at discharge was independently associated with MACEs (HR: 1.59 [95% CI: 1.03-2.45]; P=0.036) and with death (HR: 1.99 [95% CI: 1.00-3.98]; P=0.049) in multivariate analysis. More specifically, when ticagrelor prescription at discharge was compared with clopidogrel, a significant death reduction was found in both, the univariate and the multivariate Cox analysis (HR: 4.54 [95% CI: 2.26-9.13]; P<0.001 and HR: 2.61 [95% CI: 1.16-5.90]; P=0.021, respectively). CONCLUSIONS: New antiplatelet drugs, especially ticagrelor, showed lower rates of mortality in patients with CVD without differences for bleeding. Despite the recommendations of current clinical guidelines for high risk patients with ACS, the use of NADs is very low in "real-life" patients with previous CVD.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Doença das Coronárias/complicações , Doença Arterial Periférica/complicações , Inibidores da Agregação de Plaquetas/uso terapêutico , Acidente Vascular Cerebral/complicações , Síndrome Coronariana Aguda/etiologia , Síndrome Coronariana Aguda/mortalidade , Assistência ao Convalescente , Clopidogrel/efeitos adversos , Clopidogrel/uso terapêutico , Comorbidade , Uso de Medicamentos/estatística & dados numéricos , Feminino , Seguimentos , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Síndrome Metabólica/epidemiologia , Inibidores da Agregação de Plaquetas/efeitos adversos , Cloridrato de Prasugrel/uso terapêutico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fumar/epidemiologia , Espanha , Centros de Atenção Terciária/estatística & dados numéricos , Ticagrelor/efeitos adversos , Ticagrelor/uso terapêutico
11.
Eur J Clin Pharmacol ; 75(8): 1059-1068, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31081522

RESUMO

PURPOSE: High on-treatment platelet reactivity (HTPR) after clopidogrel administration in patients with acute coronary syndrome (ACS) has been associated with an increased risk of adverse events. Our previous studies reported that half-dose ticagrelor provides a similar inhibitory effect on adenosine diphosphate (ADP)-induced platelet aggregation as standard-dose ticagrelor, but half-dose of ticagrelor has not been studied in Chinese ACS patients with HTPR. This study aimed to compare the antiplatelet action of half-dose ticagrelor with high-dose clopidogrel in ACS patients with HTPR. METHODS: In this single-center randomized controlled trial, 80 (of 418 screened, 19.13%) ACS patients with HTPR while on clopidogrel were randomized to either half-dose ticagrelor (90 mg LD, then 45 mg twice daily) or high-dose clopidogrel (150 mg once daily). Platelet function was assessed by thromboelastography (TEG) and light transmission aggregometry (LTA), and adverse events were monitored throughout the study for 30 days. RESULTS: The ADP-induced platelet inhibition rate (IR) as measured by TEG was significantly higher for half-dose ticagrelor compared with high-dose clopidogrel (70.40% [61.10%-91.70%] vs. 44.25% [34.67%-79.07%], p = 0.001). The repeated HTPR rate was dramatically higher for high-dose clopidogrel compared with half-dose ticagrelor (6 of 32, 18.75% vs. 1 of 35, 2.85%; p = 0.04). No patients in either treatment group exhibited a major bleeding event or other adverse events. CONCLUSIONS: In ACS patients with HTPR, half-dose ticagrelor is more effective than high-dose clopidogrel in reducing platelet reactivity (NCT03062462).


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Clopidogrel/administração & dosagem , Inibidores da Agregação de Plaquetas/administração & dosagem , Ticagrelor/administração & dosagem , Síndrome Coronariana Aguda/sangue , Idoso , Grupo com Ancestrais do Continente Asiático , Clopidogrel/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/efeitos adversos , Testes de Função Plaquetária , Ticagrelor/efeitos adversos , Resultado do Tratamento
12.
PLoS One ; 14(5): e0216404, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31059535

RESUMO

BACKGROUND: Previous ischemic stroke is a predictor of recurrent ischemic stroke after an acute myocardial infarction (AMI). Dual antiplatelet therapy, including a P2Y12-inhibitor, is important in secondary prevention after AMI. Ticagrelor, a P2Y12-inhibitor, is more potent than the commonly used clopidogrel. Here, we evaluated the impact of ticagrelor on the risk of ischemic stroke following AMI in patients with previous ischemic stroke. METHODS: Data for patients with AMI that had a previous ischemic stroke were obtained from the Swedish Registry of Information and Knowledge about Swedish Heart Intensive Care Admissions. Patients were assigned to early and late cohorts, each covering a two-year time period before and after, respectively, the introduction of ticagrelor prescriptions (20 Dec 2011). Patients in the early cohort (n = 1633) were treated with clopidogrel (100%); those in the late cohort (n = 1642) were treated with either clopidogrel (66.3%) or ticagrelor (33.7%). We assessed the risk of ischemic stroke and intracranial bleeding over time with Kaplan-Meier analyses. We identified predictors of ischemic stroke with multivariable Cox regression analyses. RESULTS: Of 3275 patients, 311 experienced ischemic stroke after AMI. Cumulative Kaplan-Meier incidence estimates of ischemic stroke within one year after AMI were 12.1% versus 8.6% for the early and late cohorts, respectively (p<0.01). Intracranial bleeding incidences (1.2% versus 1.5%) were similar between the two cohorts. CONCLUSIONS: Ticagrelor introduction was associated with a lower rate of ischemic stroke, with no increase in intracranial bleeding, in an AMI population with a history of ischemic stroke.


Assuntos
Isquemia Encefálica , Infarto do Miocárdio , Sistema de Registros , Acidente Vascular Cerebral , Ticagrelor/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/etiologia , Isquemia Encefálica/mortalidade , Isquemia Encefálica/prevenção & controle , Clopidogrel/administração & dosagem , Clopidogrel/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/mortalidade , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/prevenção & controle , Taxa de Sobrevida , Ticagrelor/efeitos adversos
14.
Stroke ; 50(6): 1356-1363, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31092165

RESUMO

Background and Purpose- Predictors of stroke and transient ischemic attack (TIA) in patients with peripheral artery disease (PAD) are poorly understood. The primary aims of this analysis were to (1) determine the incidence of ischemic/hemorrhagic stroke and TIA in patients with symptomatic PAD, (2) identify predictors of stroke in patients with PAD, and (3) compare the rate of stroke in ticagrelor- and clopidogrel-treated patients. Methods- EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) randomized 13 885 patients with symptomatic PAD to receive monotherapy with ticagrelor or clopidogrel for the prevention of major adverse cardiovascular events (cardiovascular death, myocardial infarction, or ischemic stroke). Ischemic/hemorrhagic stroke and TIA were adjudicated and measured as incidence rates postrandomization and cumulative incidence (per patient-years). Post hoc multivariable competing risk hazards analyses were performed using baseline characteristics to determine factors associated with all-cause stroke in patients with PAD. Results- A total of 458 cerebrovascular events in 424 patients (317 ischemic strokes, 39 hemorrhagic strokes, and 102 TIAs) occurred over a median follow-up of 30 months, for a cumulative incidence of 0.87, 0.11, and 0.27 per 100 patient-years, respectively. Age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, geographic region, ankle-brachial index <0.60, prior amputation, and systolic blood pressure were independent baseline factors associated with the occurrence of all-cause stroke. After adjustment for baseline factors, the rates of ischemic stroke and all-cause stroke remained lower in patients treated with ticagrelor as compared with those receiving clopidogrel. There was no significant difference in the incidence of hemorrhagic stroke or TIA between the 2 treatment groups. Conclusions- In patients with symptomatic PAD, ischemic stroke and TIA occur frequently over time. Comorbidities such as age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, higher blood pressure, prior amputation, lower ankle-brachial index, and geographic region were each independently associated with the occurrence of all-cause stroke. Use of ticagrelor, as compared with clopidogrel, was associated with a lower adjusted rate of ischemic and all-cause stroke. Further study is needed to optimize medical management and risk reduction of all-cause stroke in patients with PAD. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01732822.


Assuntos
Clopidogrel/administração & dosagem , Hemorragias Intracranianas/prevenção & controle , Ataque Isquêmico Transitório/prevenção & controle , Doença Arterial Periférica/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle , Ticagrelor/administração & dosagem , Idoso , Clopidogrel/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Hemorragias Intracranianas/epidemiologia , Hemorragias Intracranianas/etiologia , Ataque Isquêmico Transitório/epidemiologia , Ataque Isquêmico Transitório/etiologia , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/complicações , Doença Arterial Periférica/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Ticagrelor/efeitos adversos
15.
Am Heart J ; 212: 13-22, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30928824

RESUMO

BACKGROUND: In the RE-DUAL PCI trial of patients with atrial fibrillation (AF) who underwent percutaneous coronary intervention (PCI), dabigatran dual therapy (110 or 150 mg bid, plus clopidogrel or ticagrelor) reduced International Society on Thrombosis and Haemostasis bleeding events compared with warfarin triple therapy, with noninferiority in overall thromboembolic events. This analysis assessed outcomes in relation to patient bleeding and stroke risk profiles, based on the modified HAS-BLED and CHA2DS2-VASc scores. METHODS: The primary endpoint, major bleeding event (MBE) or clinically relevant nonmajor bleeding event (CRNMBE), was compared across study arms in patients categorized by modified HAS-BLED score 0-2 or ≥3. The composite endpoint of death, thromboembolic event, and unplanned revascularization rates was compared in patients categorized by CHA2DS2-VASc score 0-1, 2, or ≥3. RESULTS: Risk of MBE or CRNMBE was lower with dabigatran dual therapy (both doses) versus warfarin triple therapy, irrespective of modified HAS-BLED category (treatment-by-subgroup interaction P-value 0.584 and 0.273 for dabigatran 110 and 150 mg dual therapy, respectively, vs warfarin). Risk of the composite thromboembolic endpoint was similar across CHA2DS2-VASc categories and consistent with overall study results (interaction P-value 0.739 and 0.075 for dabigatran 110 and 150 mg dual therapy, respectively, vs warfarin). Higher HAS-BLED scores were associated with higher risks of bleeding in AF patients after PCI in a treatment-independent analysis. CONCLUSION: Dabigatran dual therapy reduced bleeding events irrespective of bleeding risk category and demonstrated similar efficacy regardless of stroke risk category when compared with warfarin triple therapy.


Assuntos
Anticoagulantes/efeitos adversos , Fibrilação Atrial/prevenção & controle , Dabigatrana/efeitos adversos , Hemorragia/induzido quimicamente , Intervenção Coronária Percutânea , Acidente Vascular Cerebral/induzido quimicamente , Varfarina/efeitos adversos , Idoso , Anticoagulantes/uso terapêutico , Clopidogrel/efeitos adversos , Clopidogrel/uso terapêutico , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/cirurgia , Dabigatrana/uso terapêutico , Quimioterapia Combinada , Estudos de Equivalência como Asunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Tromboembolia/prevenção & controle , Ticagrelor/efeitos adversos , Ticagrelor/uso terapêutico , Varfarina/uso terapêutico
16.
Transfus Med Rev ; 33(2): 92-97, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30814031

RESUMO

Antiplatelet therapy is extensively used in the primary and secondary prophylaxis of arterial thrombotic disorders. Aspirin, the most commonly used antiplatelet agent, is a cyclooxygenase-1 inhibitor and considered a mild to moderate inhibitor of platelet function. Therefore, often a second antiplatelet agent is necessary in certain clinical conditions requiring greater inhibition of platelet function. An adenosine diphosphate (ADP) receptor, P2Y12, is an important target for this purpose; several agents inhibit this receptor providing potent antiplatelet effect. One of the side effects of these agents is bleeding, which in some patients may require reversal of antiplatelet effect. Similarly, patients undergoing emergent surgeries may benefit from reversal of antiplatelet effect to avoid excessive surgical bleeding. This article reviews current literature on this topic.


Assuntos
Hemorragia/tratamento farmacológico , Inibidores da Agregação de Plaquetas/efeitos adversos , Transfusão de Plaquetas/métodos , Aspirina/uso terapêutico , Perda Sanguínea Cirúrgica , Plaquetas/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Hemorragia/induzido quimicamente , Hemostasia/efeitos dos fármacos , Humanos , Inibidores de Fosfodiesterase/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Testes de Função Plaquetária , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Receptores Purinérgicos P2Y12/metabolismo , Tromboembolia/prevenção & controle , Ticagrelor/efeitos adversos
17.
BMC Cardiovasc Disord ; 19(1): 51, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30832574

RESUMO

OBJECTIVES: To evaluate the impact of a rapid change in preferred treatment from clopidogrel to ticagrelor on the risk of ischemic stroke following acute myocardial infarction (AMI). METHODS: Data for AMI patients treated with either clopidogrel or ticagrelor were obtained from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA). Patients were divided into two cohorts, each covering a two-year time period; the initial prescription of ticagrelor (20 Dec 2011) was used as a cut-off point. Patients in the early cohort (n = 23,447) were treated with clopidogrel, while those in the later cohort (n = 24,227), were treated with either clopidogrel (47.9%) or ticagrelor (52.1%). Kaplan-Meier analyses were used to assess the risk of ischemic stroke over time, with multivariable Cox regression analyses used to identify predictors of ischemic stroke. RESULTS: Of 47,674 patients, there were 1203 cases of ischemic stroke. Cumulative Kaplan-Meier incidence estimates of ischemic stroke after one year were 2.8% vs. 2.4% for the early and late cohorts, respectively (p = 0.001). Older age, hypertension, diabetes, previous stroke, congestive heart failure, atrial fibrillation, and ST-elevation myocardial infarction were associated with an increased risk of ischemic stroke. Percutaneous coronary intervention and statins at discharge were associated with a decreased risk of ischemic stroke, as was higher estimated glomerular filtration rate. Membership of the late cohort correlated with a 13% reduction in the relative risk of ischemic stroke. CONCLUSIONS: The introduction of ticagrelor as well as an improved management of AMI was associated with a lower rate of ischemic stroke in a relatively unselected AMI population.


Assuntos
Isquemia Encefálica/prevenção & controle , Clopidogrel/administração & dosagem , Infarto do Miocárdio/tratamento farmacológico , Inibidores da Agregação de Plaquetas/administração & dosagem , Acidente Vascular Cerebral/prevenção & controle , Ticagrelor/administração & dosagem , Idoso , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Clopidogrel/efeitos adversos , Comorbidade , Humanos , Incidência , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/epidemiologia , Inibidores da Agregação de Plaquetas/efeitos adversos , Sistema de Registros , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Suécia/epidemiologia , Ticagrelor/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
18.
Medicine (Baltimore) ; 98(11): e14833, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30882670

RESUMO

Although the new oral P2Y12 inhibitors, prasugrel/ticagrelor have shown greater efficacy than clopidogrel in patients with the acute coronary syndrome, but they have not shown better efficacy in Korean patients. So we evaluated the efficacy of the prasugrel/ticagrelor in patients with myocardial infarction (MI) and diabetes, a more high-risk patients group.From the Korea Acute Myocardial Infarction Registry-National Institute of Health, 3985 patients with MI and diabetes who underwent PCI were enrolled between November 2011 and December 2015. The patients were divided into 2 groups: clopidogrel (n = 2985) and prasugrel/ticagrelor (n = 1000).After propensity score matching, prasugrel/ticagrelor group showed a no significant difference in risk of the composite of cardiac death (CD), recurrent MI or stroke (hazard ratio [HR], 0.705; 95% confidence interval [CI], 0.474-1.048; P = .084). However, the risk of major bleeding was significantly higher in the prasugrel/ticagrelor group. (HR; 2.114, 95% CI; [1.027-4.353], P = .042). In subgroup analysis, major bleeding was significantly increased in the subgroup of creatinine clearance <60 ml/min/1.73 m, hypertension, underwent a trans-femoral approach and diagnosed as NSTEMI among the prasugrel/ticagrelor group.The use of prasugrel/ticagrelor did not improve the composite of CD, recurrent MI or stroke, however, significantly increased major bleeding events in Korean patients with MI and diabetes undergoing PCI.


Assuntos
Clopidogrel , Diabetes Mellitus , Infarto do Miocárdio , Intervenção Coronária Percutânea , Complicações Pós-Operatórias/prevenção & controle , Cloridrato de Prasugrel , Tromboembolia , Ticagrelor , Idoso , Clopidogrel/administração & dosagem , Clopidogrel/efeitos adversos , Estudos de Coortes , Comorbidade , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/métodos , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/efeitos adversos , Período Pós-Operatório , Cloridrato de Prasugrel/administração & dosagem , Cloridrato de Prasugrel/efeitos adversos , República da Coreia/epidemiologia , Tromboembolia/etiologia , Tromboembolia/prevenção & controle , Ticagrelor/administração & dosagem , Ticagrelor/efeitos adversos
19.
Ann Thorac Surg ; 107(6): 1690-1698, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30898561

RESUMO

BACKGROUND: We evaluated perioperative bleeding after coronary artery bypass grafting (CABG) in patients preoperatively treated with ticagrelor or clopidogrel, stratified by discontinuation of these P2Y12 inhibitors. METHODS: All patients from the prospective, European Multicenter Registry on Coronary Artery Bypass Grafting (E-CABG) treated with ticagrelor or clopidogrel undergoing isolated primary CABG were eligible. The primary outcome measure was severe or massive bleeding defined according to the Universal Definition of Perioperative Bleeding, stratified by P2Y12 inhibitor discontinuation. Secondary outcome measures included four additional definitions of major bleeding. Propensity score matching was performed to adjust for differences in preoperative and perioperative covariates. RESULTS: Of 2,311 patients who were included, 1,293 (55.9%) received clopidogrel and 1,018 (44.1%) ticagrelor preoperatively. Mean time between discontinuation and the operation was 4.5 ± 3.2 days for clopidogrel and 4.9 ± 3.0 days for ticagrelor. In the propensity score-matched cohort, ticagrelor-treated patients had a higher incidence of major bleeding according to Universal Definition of Perioperative Bleeding when ticagrelor was discontinued 0 to 2 days compared with 3 days before the operation (16.0% vs 2.7%, p = 0.003). Clopidogrel-treated patients had a higher incidence of major bleeding according to the Universal Definition of Perioperative Bleeding when clopidogrel was discontinued 0 to 3 days compared with 4 to 5 days before the operation (15.6% vs 8.3%, p = 0.031). CONCLUSIONS: In patients receiving ticagrelor 2 days before CABG and in those receiving clopidogrel 3 days before CABG, there was an increased rate of severe bleeding. Postponing nonemergent CABG for at least 3 days after discontinuation of ticagrelor and 4 days after clopidogrel should be considered.


Assuntos
Clopidogrel/efeitos adversos , Ponte de Artéria Coronária , Inibidores da Agregação de Plaquetas/efeitos adversos , Hemorragia Pós-Operatória/induzido quimicamente , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Ticagrelor/efeitos adversos , Idoso , Clopidogrel/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/administração & dosagem , Hemorragia Pós-Operatória/epidemiologia , Período Pré-Operatório , Estudos Prospectivos , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Ticagrelor/administração & dosagem
20.
N Engl J Med ; 380(19): 1825-1833, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-30883047

RESUMO

BACKGROUND: Ticagrelor is an oral P2Y12 inhibitor that is used with aspirin to reduce the risk of ischemic events among patients with acute coronary syndromes or previous myocardial infarction. Spontaneous major bleeding and bleeding associated with urgent invasive procedures are concerns with ticagrelor, as with other antiplatelet drugs. The antiplatelet effects of ticagrelor cannot be reversed with platelet transfusion. A rapid-acting reversal agent would be useful. METHODS: In this randomized, double-blind, placebo-controlled, phase 1 trial, we evaluated intravenous PB2452, a monoclonal antibody fragment that binds ticagrelor with high affinity, as a ticagrelor reversal agent. We assessed platelet function in healthy volunteers before and after 48 hours of ticagrelor pretreatment and again after the administration of PB2452 or placebo. Platelet function was assessed with the use of light transmission aggregometry, a point-of-care P2Y12 platelet-reactivity test, and a vasodilator-stimulated phosphoprotein assay. RESULTS: Of the 64 volunteers who underwent randomization, 48 were assigned to receive PB2452 and 16 to receive placebo. After 48 hours of ticagrelor pretreatment, platelet aggregation was suppressed by approximately 80%. PB2452 administered as an initial intravenous bolus followed by a prolonged infusion (8, 12, or 16 hours) was associated with a significantly greater increase in platelet function than placebo, as measured by multiple assays. Ticagrelor reversal occurred within 5 minutes after the initiation of PB2452 and was sustained for more than 20 hours (P<0.001 after Bonferroni adjustment across all time points for all assays). There was no evidence of a rebound in platelet activity after drug cessation. Adverse events related to the trial drug were limited mainly to issues involving the infusion site. CONCLUSIONS: In healthy volunteers, the administration of PB2452, a specific reversal agent for ticagrelor, provided immediate and sustained reversal of the antiplatelet effects of ticagrelor, as measured by multiple assays. (Funded by PhaseBio Pharmaceuticals; ClinicalTrials.gov number, NCT03492385.).


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Plaquetas/efeitos dos fármacos , Coagulantes/uso terapêutico , Inibidores da Agregação de Plaquetas , Ticagrelor/antagonistas & inibidores , Adulto , Anticorpos Neutralizantes/efeitos adversos , Plaquetas/fisiologia , Coagulantes/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Ticagrelor/efeitos adversos , Ticagrelor/uso terapêutico
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