RESUMO
OBJECTIVE: Patients with diabetes mellitus (DM) presenting with acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention (PCI) derived enhanced benefit with dual antiplatelet therapy (DAPT) with prasugrel vs. clopidogrel. The risk profile and treatment response to DAPT for medically managed ACS patients with DM remains uncertain. METHODS: The TRILOGY ACS trial compared aspirin + prasugrel vs. aspirin + clopidogrel for up to 30months in non-ST-segment elevation (NSTE) ACS patients managed medically without revascularization. We compared treatment-related outcomes among 3539 patients with DM vs. 5767 patients without DM. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. RESULTS: Patients with vs. without DM were younger, more commonly female, heavier, and more often had revascularization prior to the index ACS event. The frequency of the primary endpoint through 30months was higher among patients with vs. without DM (24.8% vs. 16.3%), with a higher risk for those patients with DM treated with insulin vs. those treated without insulin (35.3% vs. 19.9%). There was no significant difference in the frequency of the primary endpoint by treatment with prasugrel vs. clopiodgrel in those with or without DM (Pint=0.82) and with or without insulin treatment among those with DM (Pint=0.304). CONCLUSIONS: Among NSTE ACS patients managed medically without revascularization, patients with DM had a higher risk of ischemic events that was amplified among those treated with insulin. There was no differential treatment effect with a more potent DAPT regimen of aspirin + prasugrel vs. aspirin + clopidogrel.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Aspirina/administração & dosagem , Diabetes Mellitus/tratamento farmacológico , Cloridrato de Prasugrel/administração & dosagem , Ticlopidina/análogos & derivados , Idoso , Clopidogrel , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Eletrocardiografia , Feminino , Seguimentos , Humanos , Masculino , Revascularização Miocárdica , Inibidores da Agregação Plaquetária/administração & dosagem , Ticlopidina/administração & dosagem , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: There are conflicting data on whether changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) concentrations between time points (delta NT-proBNP and hs-CRP) are associated with a change in prognosis. METHODS: We measured NT-proBNP and hs-CRP at 3 time points in 1665 patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). Cox proportional hazards was applied to the delta between temporal measurements to determine the continuous association with cardiovascular events. Effect estimates for delta NT-proBNP and hs-CRP are presented per 40% increase as the basic unit of temporal change. RESULTS: Median NT-proBNP was 370.0 (25th, 75th percentiles, 130.0, 996.0), 340.0 (135.0, 875.0), and 267.0 (111.0, 684.0) ng/L; and median hs-CRP was 4.6 (1.7, 13.1), 1.9 (0.8, 4.5), and 1.8 (0.8, 4.4) mg/L at baseline, 30 days, and 6 months, respectively. The deltas between baseline and 6 months were the most prognostically informative. Every +40% increase of delta NT-proBNP (baseline to 6 months) was associated with a 14% greater risk of cardiovascular death (adjusted hazard ratio (HR) 1.14, 95% CI, 1.03-1.27) and with a 14% greater risk of all-cause death (adjusted HR 1.14, 95% CI, 1.04-1.26), while every +40% increase of delta hs-CRP (baseline to 6 months) was associated with a 9% greater risk of the composite end point (adjusted HR 1.09, 95% CI, 1.02-1.17) and a 10% greater risk of myocardial infarction (adjusted HR 1.10, 95%, CI 1.00-1.20). CONCLUSIONS: Temporal changes in NT-proBNP and hs-CRP are quantitatively associated with future cardiovascular events, supporting their role in dynamic risk stratification of NSTEACS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00699998.
Assuntos
Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/mortalidade , Biomarcadores/análise , Infarto do Miocárdio/etiologia , Proteogenômica , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/genética , Idoso , Biomarcadores/sangue , Proteína C-Reativa/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/mortalidade , Peptídeo Natriurético Encefálico/sangue , Fatores de Risco , Fatores de TempoRESUMO
AIMS: Studies have suggested increased cancer incidence associated with long-term dual antiplatelet therapy (DAPT) for acute coronary syndrome (ACS). We evaluated cancer incidence and treatment-related differences in an analysis of DAPT for ACS. METHODS AND RESULTS: The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial enrolled 9326 participants with ACS, who received aspirin plus clopidogrel or prasugrel. Median treatment exposure was 15 months. Cancer history and screening procedures were collected. Suspected non-benign neoplasm events were reported and adjudicated. The primary outcome was detection of new, non-benign neoplasm. Factors associated with neoplasm events, the relationship of these events to cardiovascular and bleeding endpoints, and treatment-related differences in neoplasm detection were studied. Among 9240 participants who received ≥1 dose of study drug, 1.8% had a confirmed neoplasm event. The efficacy composite of cardiovascular death, myocardial infarction, or stroke occurred more frequently among those with a neoplasm event vs. those without (18.2 vs. 13.5%) as did Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding (11.2 vs. 1.5%). Screening rates were substantially higher in North America and Western Europe/Scandinavia vs. other regions. Factors most strongly associated with detection of neoplasm events were older age, region, male sex, and current/recent smoking. Among the pre-specified population without a history of neoplasm or previous curative treatment for neoplasm (n = 9105), the incidence of neoplasm events was similar with prasugrel vs. clopidogrel (1.8 vs. 1.7%; HR = 1.04; 95% CI 0.77-1.42; P = 0.79). CONCLUSIONS: Neoplasm events were infrequent during long-term DAPT after ACS, were associated with differential cancer-screening practices across regions, and the frequency of neoplasm detection was similar with prasugrel vs. clopidogrel. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00699998.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Neoplasias/complicações , Infarto do Miocárdio sem Supradesnível do Segmento ST/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Cloridrato de Prasugrel/uso terapêutico , Ticlopidina/análogos & derivados , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/mortalidade , Idoso , Clopidogrel , Quimioterapia Combinada , Feminino , Hemorragia/induzido quimicamente , Hemorragia/mortalidade , Humanos , Assistência de Longa Duração , Masculino , Neoplasias/mortalidade , Infarto do Miocárdio sem Supradesnível do Segmento ST/complicações , Infarto do Miocárdio sem Supradesnível do Segmento ST/mortalidade , Ticlopidina/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: The TAXUS Liberté Post Approval Study (TL-PAS) contributed patients treated with TAXUS Liberté paclitaxel-eluting stent and prasugrel to the Dual Antiplatelet Therapy Study (DAPT) that compared 12 and 30 months thienopyridine plus aspirin therapy after drug-eluting stents. METHODS AND RESULTS: Outcomes for 2191 TL-PAS patients enrolled into DAPT were assessed. The DAPT coprimary composite end point (death, myocardial infarction [MI], or stroke) was lower with 30 compared with 12 months prasugrel treatment (3.7% versus 8.8%; hazard ratio [HR], 0.407; P<0.001). Rates of death and stroke were similar between groups, but MI was significantly reduced with prolonged prasugrel treatment (1.9% versus 7.1%; HR, 0.255; P<0.001). The DAPT coprimary end point, stent thrombosis, was also lower with longer therapy (0.2% versus 2.9%; HR, 0.063; P<0.001). MI related to stent thrombosis (0% versus 2.6%; P<0.001) and occurring spontaneously (1.9% versus 4.5%; HR, 0.407; P=0.007) were both reduced with prolonged prasugrel. MI rates increased within 90 days of prasugrel cessation after both 12 and 30 months treatment. Composite Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) moderate or severe bleeds were modestly increased (2.4% versus 1.7%; HR, 1.438; P=0.234) but severe bleeds were not more frequent (0.3% versus 0.5%; HR, 0.549; P=0.471) in the prolonged treatment group. CONCLUSIONS: Prasugrel and aspirin continued for 30 months reduced ischemic events for the TAXUS Liberté paclitaxel-eluting stent patient subset from DAPT through reductions in MI and stent thrombosis. Withdrawal of prasugrel was followed by an increase in MI after both 12 and 30 months therapy. The optimal duration of dual antiplatelet therapy with prasugrel after TAXUS Liberté paclitaxel-eluting stent remains unknown, but appears to be >30 months. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00997503.
Assuntos
Aspirina/uso terapêutico , Doença das Coronárias/terapia , Stents Farmacológicos , Paclitaxel/uso terapêutico , Piperazinas/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Tiofenos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Incidência , Internacionalidade , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Inibidores da Agregação Plaquetária/uso terapêutico , Cloridrato de Prasugrel , Piridinas/uso terapêutico , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: The role of more intense, sustained platelet inhibition in preventing stroke after acute coronary syndrome (ACS) is unclear. We observed a signal for reduced stroke risk in the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial after 12 months of treatment with prasugrel versus clopidogrel in medically managed patients with ACS. METHODS: We examined 7243 patients with ACS, aged <75 years and without prior stroke, analyzing differences in baseline characteristics between patients with and without a stroke event through 30 months with a Cox proportional hazards model. We also assessed the effect of prasugrel versus clopidogrel (plus aspirin) on risk of all stroke events and ischemic stroke over time with an extended Cox proportional hazards model. RESULTS: Stroke events were infrequent through 30 months (ischemic stroke=62; hemorrhagic stroke=15). Patients with stroke were older, had more comorbidities, and had a higher Global Registry of Acute Coronary Events (GRACE) risk score. There was a trend for a lower unadjusted frequency of all stroke events through 30 months for prasugrel versus clopidogrel: 31 (1.5%) versus 46 (2.2%); P=0.08. There was a significant treatment-by-time interaction for those with ischemic stroke (P=0.03), consistent with the 12-month landmarked Kaplan-Meier log-rank test showing a reduced hazard of ischemic stroke after 12 months with prasugrel (P=0.04). No significant interactions between treatment effect of prasugrel versus clopidogrel and time were observed for all stroke events. CONCLUSIONS: We observed a potential late treatment effect for prasugrel versus clopidogrel for a reduced risk of ischemic stroke in medically managed patients with ACS aged <75 years. These hypothesis-generating findings suggest that longer duration and more potent platelet inhibition with prasugrel may be associated with lower risk of ischemic stroke after 12 months. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00699998.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Isquemia Encefálica/prevenção & controle , Inibidores da Agregação Plaquetária/uso terapêutico , Cloridrato de Prasugrel/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Ticlopidina/análogos & derivados , Idoso , Clopidogrel , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Risco , Ticlopidina/uso terapêutico , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Sickle cell disease (SCD) is an inherited blood disorder characterized by painful vaso-occlusive crises (VOC) with limited treatment options, particularly for children. Emerging knowledge of the pathophysiology of SCD suggests antiplatelet therapies may hold promise for treatment of VOC. Multiple small studies have evaluated antiplatelet agents on the frequency of VOC with varying results, but there has not been an adequately powered study to definitively determine the effect of antiplatelet agents on VOC. Prasugrel, a third-generation thienopyridine that irreversibly inhibits platelet activation and aggregation, is approved in adults with acute coronary syndrome managed with percutaneous coronary intervention. PROCEDURE: Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) is a double-blind, randomized study with planned enrollment of >220 children from 14 countries across the Americas, Europe, Asia, and Africa, designed to test the hypothesis that prasugrel reduces the rate of VOC in children with sickle cell anemia (SCA) (homozygous hemoglobin S [HbSS] and hemoglobin Sß(0) thalassemia [HbSß(0)]). Secondary study endpoints include reductions in rate and intensity of vaso-occlusive pain as recorded in daily electronic diaries. Safety assessments include incidence of hemorrhagic events requiring medical intervention and treatment-emergent adverse events. DOVE incorporates a dose-titration strategy to reduce potential bleeding risks inherent with antiplatelet therapy while maintaining blinded treatment assignment. CONCLUSIONS: DOVE presents a unique opportunity to determine whether antiplatelet therapy reduces frequency of patient-reported VOC and daily vaso-occlusive pain in a global study of children with SCA.
Assuntos
Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Cloridrato de Prasugrel/uso terapêutico , Doenças Vasculares/prevenção & controle , Adolescente , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Dor/etiologia , Projetos de PesquisaRESUMO
BACKGROUND: The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. METHODS: In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. RESULTS: At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group. CONCLUSIONS: Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Angina Instável/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Tiofenos/uso terapêutico , Ticlopidina/análogos & derivados , Idoso , Aspirina/uso terapêutico , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Clopidogrel , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Piperazinas/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Cloridrato de Prasugrel , Antagonistas do Receptor Purinérgico P2/efeitos adversos , Antagonistas do Receptor Purinérgico P2/uso terapêutico , Acidente Vascular Cerebral/epidemiologia , Tiofenos/efeitos adversos , Ticlopidina/efeitos adversos , Ticlopidina/uso terapêuticoRESUMO
UNLABELLED: Concomitant use of proton-pump inhibitors (PPIs) has been implicated in diminished antiplatelet response to clopidogrel and an increased risk of ischemic events, but primarily among patients undergoing percutaneous coronary intervention. We sought to examine the potential influence of interactions between PPIs and clopidogrel versus prasugrel on platelet reactivity and clinical outcomes after acute coronary syndromes (ACS) in patients managed medically without revascularization. METHODS: This analysis from the TRILOGY ACS trial focused upon the 7,243 ACS patients aged <75 years who were managed without revascularization, randomized to clopidogrel or prasugrel, and followed for a median of 17 months. Proton-pump inhibitor type and use were assessed at each study visit, and 2,049 of the patients in this cohort underwent serial platelet reactivity assessments. RESULTS: Proton-pump inhibitor use (23%) was similar between the clopidogrel and prasugrel groups at baseline and throughout the study. Median on-treatment platelet reactivity values were consistently lower with prasugrel versus clopidogrel irrespective of PPI use. For the primary end point (composite of cardiovascular death, myocardial infarction [MI], or stroke), PPI use modified the unadjusted treatment effect of prasugrel versus clopidogrel (interaction P = .02). After adjusting for differences in baseline characteristics, this treatment effect modification was attenuated for the composite end point (interaction P = .06) but was significant for the MI component end point (interaction P = .01). Similarly, among patients on a PPI, the frequency of MI was significantly lower with prasugrel versus clopidogrel (hazard ratio = 0.61; 95% CI 0.42-0.88). These findings were similar by PPI type (omeprazole and pantoprazole). CONCLUSIONS: Among ACS patients managed without revascularization, use of PPIs did not result in a differential antiplatelet response between prasugrel versus clopidogrel but was associated with a lower incidence of MI with prasugrel. These hypothesis-generating findings suggest that factors besides platelet reactivity may underlie the differential risk of MI observed by treatment assignment with PPI use.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Ativação Plaquetária/efeitos dos fármacos , Cloridrato de Prasugrel/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Ticlopidina/análogos & derivados , Síndrome Coronariana Aguda/sangue , Idoso , Clopidogrel , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/administração & dosagem , Guias de Prática Clínica como Assunto , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Ticlopidina/administração & dosagem , Fatores de Tempo , Resultado do TratamentoRESUMO
INTRODUCTION: This phase 2 study was designed to characterize the relationship among prasugrel dose, prasugrel's active metabolite (Pras-AM), and platelet inhibition while evaluating safety in children with sickle cell disease. It was open-label, multicenter, adaptive design, dose ranging, and conducted in 2 parts. Part A: Patients received escalating single doses leading to corresponding increases in Pras-AM exposure and VerifyNow®P2Y12 (VN) platelet inhibition and decreases in VNP2Y12 reaction units and vasodilator-stimulated phosphoprotein platelet reactivity index. Part B: Patients were assigned daily doses (0.06, 0.08, and 0.12 mg/kg) based on VN pharmacodynamic measurements at the start of 2 dosing periods, each 14±4 days. Platelet inhibition was significantly higher at 0.12 mg/kg (56.3%±7.4%; least squares mean±SE) compared with 0.06 mg/kg (33.8%±7.4%) or 0.08 mg/kg (37.9%±5.6%). Patients receiving 0.12 mg/kg achieved ≥30% platelet inhibition; only 1 patient receiving 0.06 mg/kg exceeded 60% platelet inhibition. High interpatient variability in response to prasugrel and the small range of exposures precluded rigorous characterization of the relationship among dose, Pras-AM, and platelet inhibition. SAFETY: No hemorrhagic events occurred in Part A; 3 occurred in Part B, all mild and self-limited. CONCLUSIONS: Most children with sickle cell disease may achieve clinically relevant platelet inhibition with titration of daily-dose prasugrel.
Assuntos
Anemia Falciforme/tratamento farmacológico , Piperazinas/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Tiofenos/farmacologia , Adolescente , Anemia Falciforme/sangue , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Modelos Biológicos , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Cloridrato de Prasugrel , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Projetos de Pesquisa , Tiofenos/efeitos adversos , Tiofenos/farmacocinéticaRESUMO
Platelets of patients with sickle cell disease (SCD) show evidence of mild activation in the non-crisis steady state and greater activation during vaso-occlusive crises (VOC). Prasugrel, a potent inhibitor of ADP-mediated platelet activation and aggregation, may be useful in attenuating VOC. We compared platelet responses to ADP stimulation in patients with SCD and healthy subjects before and after treatment with prasugrel. In a phase 1 study, platelet biomarker levels were assessed in 12 adult patients with SCD and 13 healthy subjects before and after 12 ± 2 days of 5.0 or 7.5 mg/day prasugrel. The following were determined in whole blood samples stimulated with 20 µM ADP: (i) percentages of monocytes and neutrophils with adherent platelets (cell-platelet aggregates); (ii) the relative number (mass) of platelets associated with each monocyte and neutrophil as reported by CD61 mean fluorescence intensity (MFI) of the monocyte-platelet and neutrophil-platelet aggregates; (iii) the percentages of platelets positive for surface expression of CD40 ligand (CD40L), P-selectin (CD62p) and activated glycoprotein IIb-IIIa (GPIIb-IIIa); and (iv) the percentages of platelets and monocyte-platelet aggregates positive for surface tissue factor (TF) expression. At baseline, there were no significant differences between cohorts in the percentages of platelets expressing activation biomarkers. Following 12 days of prasugrel administration, the percentages of platelets expressing activation biomarkers following ADP stimulation were reduced in both cohorts, and there were no significant differences between groups. Both patients with SCD and healthy subjects had significant reductions in the monocyte-platelet and neutrophil-platelet aggregate MFI and the percentage of platelets expressing P-selectin and activated GPIIb-IIIa (all p < 0.05). Healthy subjects also had significant reductions in monocyte-platelet aggregate percentages (p = 0.004), neutrophil-platelet aggregate percentages (p = 0.011) and the percentage of CD40L-positive platelets (p = 0.044) that were not observed in patients with SCD. Prasugrel administration to SCD patients attenuates ex vivo ADP-stimulated platelet activation as measured by the percentage of platelets positive for P-selectin and GPIIb-IIIa, thus reducing the proportion of platelets that may participate in aggregates. Furthermore, prasugrel decreases ex vivo ADP-stimulated platelet aggregation with monocytes and neutrophils as measured by the monocyte-platelet and neutrophil-platelet aggregate MFI. This implies that in the presence of prasugrel, fewer platelets adhere to monocytes and neutrophils, which may result in reducing cell-platelet aggregate size. Therefore, reduced platelet reactivity and decreased size of leukocyte-platelet aggregates suggest additional mechanisms by which prasugrel may provide benefit to patients with SCD and support further investigation of possible therapeutic benefits of prasugrel in this population.
Assuntos
Difosfato de Adenosina/metabolismo , Anemia Falciforme/sangue , Anemia Falciforme/tratamento farmacológico , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Cloridrato de Prasugrel/uso terapêutico , Difosfato de Adenosina/farmacologia , Adulto , Biomarcadores , Estudos de Casos e Controles , Feminino , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/farmacologia , Cloridrato de Prasugrel/farmacologia , Adulto JovemRESUMO
BACKGROUND: Dual antiplatelet therapy in older versus younger patients with acute coronary syndromes is understudied. Low-dose prasugrel (5 mg/d) is recommended for younger, lower-body-weight patients and elderly patients with acute coronary syndromes to mitigate the bleeding risk of standard-dose prasugrel (10 mg/d). METHODS AND RESULTS: A total of 9326 medically managed patients with acute coronary syndromes from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial (<75 years of age, n=7243; ≥75 years of age, n=2083) were randomized to prasugrel (10 mg/d; 5 mg/d for those ≥75 or <75 years of age and <60 kg in weight) or clopidogrel (75 mg/d) plus aspirin for ≤30 months. A total of 515 participants ≥75 years of age (25% of total elderly population) had serial platelet reactivity unit measurements in a platelet-function substudy. Cumulative risks of the primary end point (cardiovascular death/myocardial infarction/stroke) and Thrombolysis in Myocardial Infarction (TIMI) major bleeding increased progressively with age and were ≥2-fold higher in older participants. Among those ≥75 years of age, TIMI major bleeding (4.1% versus 3.4%; hazard ratio, 1.09; 95% confidence interval, 0.57-2.08) and the primary end point rates were similar with reduced-dose prasugrel and clopidogrel. Despite a correlation between lower 30-day on-treatment platelet reactivity unit values and lower weight only in the prasugrel group, there was a nonsignificant treatment-by-weight interaction for platelet reactivity unit values among participants ≥75 years of age in the platelet-function substudy (P=0.06). No differences in weight were seen in all participants ≥75 years of age with versus without TIMI major/minor bleeding in both treatment groups. CONCLUSIONS: Older age is associated with substantially increased long-term cardiovascular risk and bleeding among patients with medically managed acute coronary syndromes, with no differences in ischemic or bleeding outcomes with reduced-dose prasugrel compared with clopidogrel in elderly patients. No significant interactions among weight, pharmacodynamic response, and bleeding risk were observed between reduced-dose prasugrel and clopidogrel in elderly patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov/ct2/home. Unique identifier: NCT0069999.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Aspirina/uso terapêutico , Gerenciamento Clínico , Piperazinas/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Tiofenos/uso terapêutico , Ticlopidina/análogos & derivados , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Aspirina/efeitos adversos , Clopidogrel , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Hemorragia/epidemiologia , Hemorragia/prevenção & controle , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Piperazinas/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Cloridrato de Prasugrel , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Fatores de Risco , Tiofenos/efeitos adversos , Ticlopidina/efeitos adversos , Ticlopidina/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Treatment with prasugrel and aspirin improves outcomes compared with clopidogrel and aspirin for patients with acute coronary syndrome who have had angiography and percutaneous coronary intervention; however, no clear benefit has been shown for patients managed first with drugs only. We assessed outcomes from the TRILOGY ACS trial based on whether or not patients had coronary angiography before treatment was chosen. METHODS: TRILOGY ACS (ClinicalTrials.gov number NCT00699998) was a randomised controlled trial, done at more than 800 sites worldwide. Patients with non-ST-elevation acute coronary syndrome who were selected for management without [corrected] revascularisation were randomly assigned to clopidogrel or prasugrel.The primary endpoint was cardiovascular death, myocardial infarction, or stroke at 30 months. In the present analysis we assessed differences in the primary endpoint by angiography status and whether the effects of treatment on the primary endpoint differed between patients who had angiography before enrolment and those who had not. FINDINGS: 7243 patients younger than 75 years were included in the TRILOGY ACS primary analysis. 3085 (43%) had angiography at baseline, 4158 (57%) had not. Fewer patients who had angiography reached the primary endpoint at 30 months compared with those who did not have angiography, according to Kaplan-Meier analysis (281/3085 [12·8%] vs 480/4158 [16·5%], adjusted hazard ratio [HR] 0·63, 95% CI 0·53-0·75; p<0·0001). The proportion of patients who reached the primary endpoint was lower in the prasugrel group than in the clopidogrel group for those who had angiography (122/1524 [10·7%] vs 159/1561 [14·9%], HR 0·77, 95% CI 0·61-0·98; p=0·032) but did not differ between groups in patients who did not have angiography (242/2096 [16·3%] vs 238/2062 [16·7%], HR 1·01, 0·84-1·20; p=0·94; pinteraction=0·08). Overall, TIMI major bleeding and GUSTO severe bleeding were rare. Bleeding outcomes tended to be higher with prasugrel but did not differ significantly between treatment groups in either angiography cohort. INTERPRETATION: Among patients who had angiography who took prasugrel there were fewer cardiovascular deaths, myocardial infarctions, or strokes than in those who took clopidogrel. This result needs to be corroborated, but it is consistent with previous trials of more versus less intensive antiplatelet treatment. When angiography is done for acute coronary syndrome and anatomic coronary disease confirmed, the benefits and risks of intensive antiplatelet treatment exist whether the patient is treated with drugs or percutaneous coronary intervention. FUNDING: Daiichi Sankyo, Eli Lilly.
Assuntos
Angina Instável/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Tiofenos/uso terapêutico , Ticlopidina/análogos & derivados , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/mortalidade , Idoso , Angina Instável/mortalidade , Clopidogrel , Angiografia Coronária , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/prevenção & controle , Cloridrato de Prasugrel , Fatores de Risco , Acidente Vascular Cerebral/prevenção & controle , Ticlopidina/uso terapêutico , Resultado do TratamentoRESUMO
Body weight is a predictor of clopidogrel response. However, no prospective studies have compared pharmacodynamic (PD) and pharmacokinetic (PK) data based on body weight. We compared PD and PK effects of clopidogrel 75 mg in low body weight (LBW, <60 kg) and higher body weight (HBW, ≥60 kg) patients with stable coronary artery disease. LBW (n = 34, 56.4 ± 3.7 kg) and HBW (n = 38, 84.7 ± 14.9 kg) aspirin-treated patients received clopidogrel 75 mg for 10-14 days. The area under the concentration-time curve of active metabolite (Clop-AM) calculated through the last quantifiable concentration up to 4 h postdose, AUC(0-tlast), was calculated by noncompartmental methods. Light transmission aggregometry (LTA) (maximum platelet aggregation and inhibition of platelet aggregation to 20 µM adenosine diphosphate (ADP), and residual platelet aggregation to 5 µM ADP), VerifyNow(®) P2Y12 reaction units (PRU), and vasodilator-associated stimulated phosphoprotein phosphorylation platelet reactivity index (VASP-PRI) were performed. Mean AUC(0-tlast) was lower in HBW than LBW patients: 12.8 versus 17.9 ng h/mL. HBW patients had higher platelet reactivity as measured by LTA (all p ≤ 0.01), PRU (207 ± 68 vs. 152 ± 57, p < 0.001), and VASP-PRI (56 ± 18 vs. 39 ± 17, p < 0.001). More HBW patients exhibited high on-treatment platelet reactivity (HPR) using PRU (35 vs. 9%) and VASP-PRI (65 vs. 27%). Body weight correlated with PRU and VASP-PRI (both p < 0.001), and inversely with log transformed AUC(0-tlast) (p < 0.001). In conclusion, HBW patients had lower levels of Clop-AM, and higher platelet reactivity and rates of HPR than LBW subjects, contributing to their suboptimal response to clopidogrel.
Assuntos
Peso Corporal , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacocinética , Ticlopidina/análogos & derivados , Adolescente , Adulto , Idoso , Plaquetas/metabolismo , Clopidogrel , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Ticlopidina/administração & dosagem , Ticlopidina/farmacocinéticaRESUMO
AIMS: Prasugrel is a novel thienopyridine P2Y12 adenosine diphosphate (ADP) receptor antagonist that inhibits ADP-mediated platelet activation and aggregation. Accordingly, it may be useful in reducing platelet-related ischaemia in sickle cell disease (SCD). Exposure to prasugrel's active metabolite (Pras-AM) and its antiplatelet activity in SCD have not been investigated. METHODS: Thirteen adult patients with SCD and an equal number of matched healthy control subjects were studied before and after 12 days of 5.0 or 7.5 mg day(-1) prasugrel treatment. Platelet reactivity was assessed by light transmission aggregometry (LTA), impedance aggregometry (MEA), VerifyNow® P2Y12, vasodilator-stimulated phosphoprotein (VASP) phosphorylation and Plateletworks. Exposure to Pras-AM was also assessed. RESULTS: At baseline, patients with SCD showed increased platelet reactivity vs. healthy control subjects with VerifyNow (408 vs. 323 P2Y12 reaction units (PRU), respectively, P = 0.003) and MEA (106 vs. 77 area under the aggregation curve (AU.min), P = 0.002); lower platelet reactivity index with VASP flow cytometry (59 vs. 79% platelet reactivity index (PRI), P = 0.018); and no significant differences with LTA, VASP enzyme-linked immunosorbent assay or Plateletworks. Relative to baseline, prasugrel significantly reduced platelet reactivity by all assays in both populations (all P < 0.05). Prasugrel was well tolerated, with no bleeding-related events in patients with SCD. The mean concentration-time profiles of Pras-AM were comparable between healthy subjects and patients with SCD following a single 10 mg prasugrel dose and following the 12th dose of 7.5 or 5 mg prasugrel. CONCLUSIONS: Results demonstrate that in response to prasugrel, patients with SCD and healthy subjects have similar degrees of platelet inhibition and exposure to Pras-AM, and provide a basis for further study of prasugrel in patients with SCD.
Assuntos
Anemia Falciforme/metabolismo , Plaquetas/efeitos dos fármacos , Piperazinas/farmacocinética , Antagonistas do Receptor Purinérgico P2/farmacocinética , Tiofenos/farmacocinética , Adulto , Anemia Falciforme/tratamento farmacológico , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Masculino , Piperazinas/efeitos adversos , Piperazinas/farmacologia , Testes de Função Plaquetária , Cloridrato de Prasugrel , Antagonistas do Receptor Purinérgico P2/efeitos adversos , Antagonistas do Receptor Purinérgico P2/farmacologia , Tiofenos/efeitos adversos , Tiofenos/farmacologia , Adulto JovemRESUMO
UNLABELLED: Prasugrel results in greater platelet inhibition compared to clopidogrel which may prolong the time to platelet P2Y(12) receptor function recovery following drug cessation after loading dose (LD) administration. This randomized study assessed the time to recovery of platelet function in patients with coronary artery disease after a LD of prasugrel or clopidogrel. Enrolled patients (n = 21) received either prasugrel (30 mg or 60 mg) or clopidogrel (600 mg) in preparation for coronary angiography. Platelet function was assessed by the VerifyNow P2Y12 assay, Multiplate and LTA at baseline and over time (1, 3, 5, 7, 9, and 11 days) post-LD treatment. Recovery of platelet function was defined as occurring on the first day that P2Y12 reaction units were ≤60 below pre-drug values and remained in this range. The relationship between platelet inhibition at 24 h post-LD to time of recovery was also evaluated. Recovery of platelet function occurred from days 3-7 for clopidogrel-treated subjects, by day 7 for patients treated with prasugrel 30 mg and from days 7-9 for patients treated with prasugrel 60 mg. Time for platelet function to return to baseline was independent of treatment assignment, reflecting instead the extent of platelet inhibition at 24 h post-LD (correlation coefficient = 0.81, p < 0.001), which was greater following a prasugrel LD. CONCLUSIONS: Prasugrel-treated subjects require a longer time for recovery compared with clopidogrel due to greater post-LD platelet inhibition. Platelet function testing after cessation of P2Y(12) receptor blockers may prove useful to guide the timing of surgical procedures (clinicaltrials.gov identifier: NCT01107899).
Assuntos
Plaquetas/efeitos dos fármacos , Doença da Artéria Coronariana/tratamento farmacológico , Piperazinas/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Tiofenos/administração & dosagem , Ticlopidina/análogos & derivados , Idoso , Clopidogrel , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Piperazinas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/farmacologia , Testes de Função Plaquetária , Cloridrato de Prasugrel , Tiofenos/efeitos adversos , Tiofenos/farmacologia , Ticlopidina/administração & dosagem , Ticlopidina/efeitos adversos , Ticlopidina/farmacologia , Resultado do TratamentoRESUMO
BACKGROUND: Observational studies of new coronary stents are necessary to assess performance in a variety of complex patient and lesion types. Furthermore, the optimal dose and duration of thienopyridine treatment is unclear, particularly in patients with complex clinical conditions. The TAXUS Liberte Post-Approval Study is designed to provide 5-year data on the TAXUS Liberté paclitaxel-eluting stent with concomitant prasugrel therapy in routine clinical practice and to contribute data to the DAPT study. STUDY DESIGN: The TAXUS Liberte Post-Approval Study is a prospective, multicenter, observational study. Enrollment of approximately 4,200 patients receiving ≥1 TAXUS Liberté stents is planned. All patients without a contraindication will be prescribed prasugrel plus aspirin for 1 year. The 12-month primary end point of cardiac death or myocardial infarction in on-label stent patients will be compared with historical TAXUS Express stent data from the TAXUS ATLAS and TAXUS ARRIVE studies. Secondary clinical end points include stent thrombosis, all-cause death, stroke, revascularization, and bleeding in all patients. In addition, this study will be the first to evaluate prasugrel use in a routine practice setting (including 5 and 10 mg daily doses) and will contribute data to the DAPT Study, comparing 12 versus 30 months of dual antiplatelet therapy after drug-eluting stent placement. SUMMARY: The TAXUS Liberte Post-Approval Study will be the first to provide long-term real-world data on use of the TAXUS Liberté Stent with prasugrel treatment. The study is currently enrolling, and primary end point data are expected in mid 2013.
Assuntos
Doença da Artéria Coronariana/terapia , Stents Farmacológicos/normas , Piperazinas/uso terapêutico , Tiofenos/uso terapêutico , Idoso , Cardiologia/métodos , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Reestenose Coronária/prevenção & controle , Aprovação de Equipamentos , Desenho de Equipamento , Feminino , Seguimentos , Humanos , Masculino , Cloridrato de Prasugrel , Estudos Prospectivos , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Fatores de Tempo , Resultado do TratamentoRESUMO
AIMS: This open-label, two-period, randomized, crossover study was designed to determine the effect of CYP2C19 reduced function variants on exposure to active metabolites of, and platelet response to, prasugrel and clopidogrel. METHODS: Ninety healthy Chinese subjects, stratified by CYP2C19 phenotype, were randomly assigned to treatment with prasugrel 10 mg or clopidogrel 75 mg for 10 days followed by 14 day washout and 10 day treatment with the other drug. Eighty-three subjects completed both treatment periods. Blood samples were collected at specified time points for measurement of each drug's active metabolite (Pras-AM and Clop-AM) concentrations and determination of inhibition of platelet aggregation (IPA) by light transmittance aggregometry. CYP2C19 genotypes were classified into three predicted phenotype groups: rapid metabolizers [RMs (*1/*1)], heterozygous or intermediate metabolizers [IMs (*1/*2, *1/*3)] and poor metabolizers [PMs (*2/*2, *2/*3)]. RESULTS: Pras-AM exposure was similar in IMs and RMs (90% CI 0.85, 1.03) and slightly lower in PMs than IMs (90% CI 0.74, 0.99), whereas Clop-AM exposure was significantly lower in IMs compared with RMs (90% CI 0.62, 0.83), and in PMs compared with IMs (90% CI 0.53, 0.82). IPA was more consistent among RMs, IMs and PMs in prasugrel treated subjects (80.2%, 84.2% and 80.2%, respectively) than in clopidogrel treated subjects (59.7%, 56.2% and 36.8%, respectively; P < 0.001). CONCLUSIONS: Prasugrel demonstrated higher active metabolite exposure and more consistent pharmacodynamic response across all three predicted phenotype groups compared with clopidogrel, confirming observations from previous research that CYP2C19 phenotype plays an important role in variability of response to clopidogrel, but has no impact on response to prasugrel.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Piperazinas/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Tiofenos/farmacologia , Ticlopidina/análogos & derivados , Adulto , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Clopidogrel , Estudos Cross-Over , Citocromo P-450 CYP2C19 , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Masculino , Linhagem , Piperazinas/farmacocinética , Agregação Plaquetária/genética , Inibidores da Agregação Plaquetária/farmacocinética , Polimorfismo Genético/genética , Cloridrato de Prasugrel , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Tiofenos/farmacocinética , Ticlopidina/farmacocinética , Ticlopidina/farmacologia , Adulto JovemRESUMO
The purpose of this analysis was to determine the time by which a prasugrel 60-mg loading dose (LD) achieved significantly greater inhibition of platelet aggregation (IPA) than the peak IPA after a clopidogrel 300-mg LD or 600-mg LD. Data were pooled from nine studies representing 587 individuals: 274 healthy subjects and 313 patients with stable coronary artery disease. The primary pharmacodynamic measure was IPA using 20 [mu]M adenosine-5'-diphosphate as the agonist. Gatekeeping analysis compared the peak IPA at 4, 6, and 24 hours after a clopidogrel 300-mg or 600-mg LD with IPA at various prior time points backwards after a prasugrel LD until a statistically nonsignificant difference was reached. Prasugrel 60-mg LD produced greater IPA by 30 minutes than the peak IPA after a clopidogrel 300-mg LD (P < 0.0001). Significantly greater IPA was achieved at 1 hour after prasugrel 60-mg LD compared with the peak IPA after 600-mg clopidogrel LD (P < 0.0001), regardless of sex, body weight, or age and as early as 30 minutes in the diabetic subgroup. A prasugrel 60-mg LD produces significantly faster onset and greater IPA compared with a clopidogrel 300-mg LD or 600-mg LD.
Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Piperazinas/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Tiofenos/farmacologia , Ticlopidina/análogos & derivados , Clopidogrel , Estudos Cross-Over , Interpretação Estatística de Dados , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Piperazinas/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Cloridrato de Prasugrel , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Tiofenos/administração & dosagem , Ticlopidina/administração & dosagem , Ticlopidina/farmacologia , Fatores de TempoRESUMO
We compared platelet function results obtained with the VerifyNow P2Y12 (VN-P2Y12) point-of-care device and the light transmission aggregometry (5 and 20 microM adenosine diphosphate) method using an integrated database of eight clinical trials with a total of 591 subjects. The study was performed in healthy subjects, patients with coronary artery disease, patients with end-stage renal disease, and patients with acute coronary syndrome after treatment with prasugrel or clopidogrel. Analyses focused on loading doses of 60 mg prasugrel or 600 mg clopidogrel and daily maintenance doses of 10 mg prasugrel or 75 or 150 mg clopidogrel. Similar patterns of platelet inhibition were observed for light transmission aggregometry versus VN-P2Y12 and assay results were well correlated (r approximately 0.7), although a sigmoidal model may more accurately represent the relationship between light transmission aggregometry and VN-P2Y12, because VN-P2Y12 was relatively less sensitive to low and high levels of inhibition. The percentage of poor responders was less with prasugrel compared with clopidogrel by both assays, but the percentages tended to differ between the assays. The VN-P2Y12 "BASE" channel appeared to be susceptible to high levels of P2Y12 blockade, which would underestimate the VN-P2Y12-reported percent inhibition in individuals who respond well to loading doses of thienopyridines. This integrated analysis supports the findings of earlier individual studies comparing these methodologies that assess platelet function.