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1.
N Engl J Med ; 369(11): 999-1010, 2013 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-23991622

RESUMEN

BACKGROUND: Although P2Y12 antagonists are effective in patients with non-ST-segment elevation (NSTE) acute coronary syndromes, the effect of the timing of administration--before or after coronary angiography--is not known. We evaluated the effect of administering the P2Y12 antagonist prasugrel at the time of diagnosis versus administering it after the coronary angiography if percutaneous coronary intervention (PCI) was indicated. METHODS: We enrolled 4033 patients with NSTE acute coronary syndromes and a positive troponin level who were scheduled to undergo coronary angiography within 2 to 48 hours after randomization. Patients were randomly assigned to receive prasugrel (a 30-mg loading dose) before the angiography (pretreatment group) or placebo (control group). When PCI was indicated, an additional 30 mg of prasugrel was given in the pretreatment group at the time of PCI and 60 mg of prasugrel was given in the control group. RESULTS: The rate of the primary efficacy end point, a composite of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy (glycoprotein IIb/IIIa bailout) through day 7, did not differ significantly between the two groups (hazard ratio with pretreatment, 1.02; 95% confidence interval [CI], 0.84 to 1.25; P=0.81). The rate of the key safety end point of all Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, whether related or not related to coronary-artery bypass grafting (CABG), through day 7 was increased with pretreatment (hazard ratio, 1.90; 95% CI, 1.19 to 3.02; P=0.006). The rates of TIMI major bleeding and life-threatening bleeding not related to CABG were increased by a factor of 3 and 6, respectively. Pretreatment did not reduce the rate of the primary outcome among patients undergoing PCI (69% of the patients) but increased the rate of TIMI major bleeding at 7 days. All the results were confirmed at 30 days and in prespecified subgroups. CONCLUSIONS: Among patients with NSTE acute coronary syndromes who were scheduled to undergo catheterization, pretreatment with prasugrel did not reduce the rate of major ischemic events up to 30 days but increased the rate of major bleeding complications. (Funded by Daiichi Sankyo and Eli Lilly; ACCOAST ClinicalTrials.gov number, NCT01015287.).


Asunto(s)
Síndrome Coronario Agudo/tratamiento farmacológico , Angiografía Coronaria , Piperazinas/administración & dosificación , Premedicación , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Tiofenos/administración & dosificación , Síndrome Coronario Agudo/terapia , Anciano , Puente de Arteria Coronaria , Método Doble Ciego , Femenino , Hemorragia/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/tratamiento farmacológico , Intervención Coronaria Percutánea , Piperazinas/efectos adversos , Clorhidrato de Prasugrel , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Tiofenos/efectos adversos
2.
Thromb Haemost ; 109(2): 347-55, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23223867

RESUMEN

The prevalence of high platelet reactivity (HPR) in patients who have switched from clopidogrel to prasugrel during maintenance phase after an acute coronary syndrome (ACS) event is unknown. Therefore, the effect of switching from clopidogrel to prasugrel on the prevalence of HPR was evaluated. This analysis from the previously reported SWAP (SWitching Anti Platelet) study assessed HPR at baseline, 2 and 24 hours, and seven days after switching from clopidogrel to prasugrel maintenance dose (MD), with or without a prasugrel loading dose (LD) using four definitions: maximum platelet aggregation (MPA) >65% (primary endpoint), MPA >50%, P2Y12 reaction units (PRU) >235, and platelet reactivity index (PRI) ≥ 50%. A total of 95 patients were available for analysis; 56 patients provided DNA for genetic assessments of cytochrome P450 (CYP) 2C19. There were 26 (27.4%) patients with HPR at the end of the clopidogrel run-in (defined as MPA >65%). The HPR prevalence varied by each definition and ranged from 19% (PRU >235) to 68% (PRI ≥ 50 %). A significantly higher HPR prevalence was observed during clopidogrel versus the combined prasugrel therapy groups at seven days as measured by MPA >65% (21.2% vs. 4.5%, p<0.05), PRU >235 (18.8% vs. 0%, p=0.001), and PRI ≥ 50 % (66.7% vs. 7.9%, p<0.0001). There was a significantly higher percentage of subjects carrying at least one reduced function allele with HPR measured by MPA >65% (p=0.02) or PRU >235 (p=0.05) than non-carriers with HPR. Switching ACS patients during maintenance clopidogrel therapy to prasugrel with or without an LD is associated with a reduced HPR prevalence and may provide an alternative strategy to treat patients with HPR, independent of CYP2C19 genotype.


Asunto(s)
Síndrome Coronario Agudo/tratamiento farmacológico , Sustitución de Medicamentos , Piperazinas/administración & dosificación , Inhibidores de Agregación Plaquetaria/administración & dosificación , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Tiofenos/administración & dosificación , Ticlopidina/análogos & derivados , Síndrome Coronario Agudo/sangre , Anciano , Hidrocarburo de Aril Hidroxilasas/genética , Hidrocarburo de Aril Hidroxilasas/metabolismo , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Moléculas de Adhesión Celular/sangre , Clopidogrel , Citocromo P-450 CYP2C19 , Método Doble Ciego , Femenino , Genotipo , Humanos , Masculino , Proteínas de Microfilamentos/sangre , Persona de Mediana Edad , Farmacogenética , Fenotipo , Fosfoproteínas/sangre , Piperazinas/efectos adversos , Piperazinas/metabolismo , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/metabolismo , Pruebas de Función Plaquetaria , Clorhidrato de Prasugrel , Estudios Prospectivos , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Antagonistas del Receptor Purinérgico P2Y/metabolismo , Receptores Purinérgicos P2Y12/sangre , Receptores Purinérgicos P2Y12/efectos de los fármacos , Tiofenos/efectos adversos , Tiofenos/metabolismo , Ticlopidina/administración & dosificación , Ticlopidina/efectos adversos , Ticlopidina/metabolismo , Resultado del Tratamiento
3.
Thromb Haemost ; 106(2): 219-26, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21713327

RESUMEN

It was the objective of this study to determine whether the intrinsic platelet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade by prasugrel (60 mg loading dose [LD]), 10 mg daily maintenance dose [MD]) or high-dose clopidogrel (600 mg LD, 150 mg daily MD). High residual platelet function during clopidogrel therapy is associated with poor clinical outcomes. It remains unknown whether the relationship between platelet reactivity prior to treatment with clopidogrel (300 mg LD, 75 mg daily MD) and residual on-treatment platelet reactivity is maintained after more potent P2Y12 inhibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, two-phase crossover study of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned percutaneous coronary intervention. ADP-stimulated platelet-monocyte aggregates, platelet surface P-selectin and platelet aggregation were measured pre-treatment, during LD (6 h and 18-24 h) and MD (15 d). Correlations of pre-treatment to on-treatment values were determined by Spearman rank order. Prasugrel resulted in greater platelet inhibition than high-dose clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h, 18-24 h and 15 day reactivity to ADP (correlations 0.24-0.62 for platelet-monocyte aggregates and P-selectin). In conclusion, a patient's intrinsic platelet response to ADP before exposure to thienopyridines contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade with high-dose clopidogrel or even higher level P2Y12 blockade with prasugrel. Patients who are hyper-responsive to ADP pre-treatment are more likely to be hyper-responsive to ADP on-treatment, which may be relevant to therapeutic strategies.


Asunto(s)
Piperazinas/administración & dosificación , Inhibidores de Agregación Plaquetaria/administración & dosificación , Antagonistas del Receptor Purinérgico P2/administración & dosificación , Tiofenos/administración & dosificación , Ticlopidina/análogos & derivados , Adenosina Difosfato/farmacología , Anciano , Clopidogrel , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factor de Activación Plaquetaria/efectos de los fármacos , Factor de Activación Plaquetaria/fisiología , Clorhidrato de Prasugrel , Receptores Purinérgicos P2Y12/efectos de los fármacos , Ticlopidina/administración & dosificación
4.
J Am Coll Cardiol ; 56(13): 1017-23, 2010 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-20846599

RESUMEN

OBJECTIVES: The objective was to evaluate the pharmacodynamic response of switching patients on maintenance phase clopidogrel therapy after an acute coronary syndrome (ACS) to prasugrel. BACKGROUND: Prasugrel P2Y(12) receptor blockade is associated with greater pharmacodynamic platelet inhibition and reduction of ischemic complications compared with that of clopidogrel in ACS patients undergoing percutaneous coronary intervention. The pharmacodynamic effects of switching patients during maintenance phase clopidogrel therapy after an ACS event to prasugrel are unknown. METHODS: The SWAP (SWitching Anti Platelet) study was a phase 2, multicenter, randomized, double-blind, double-dummy, active-control trial. After a run-in of daily open-label clopidogrel 75 mg with aspirin therapy for 10 to 14 days, patients were randomly assigned to 1 of the following 3 treatments: placebo loading dose (LD)/clopidogrel 75 mg maintenance dose (MD), placebo LD/prasugrel 10 mg MD, or prasugrel 60 mg LD/10 mg MD. Platelet function was evaluated at 2 h, 24 h, 7 days, and 14 days using light transmittance aggregometry, VerifyNow P2Y(12) assay, and vasodilator-stimulated phosphoprotein phosphorylation. RESULTS: A total of 139 patients were randomized, of whom 100 were eligible for analysis. Maximum adenosine diphosphate-induced platelet aggregation (20 µM) by light transmittance aggregometry at 1 week (primary end point) was lower after prasugrel MD compared with clopidogrel MD (41.1% vs. 55.0%, p < 0.0001), and was also lower in the prasugrel LD+MD group compared with clopidogrel MD (41.0% vs. 55.0%, p < 0.0001). At 2 h, a prasugrel LD resulted in higher platelet inhibition compared with the other regimens. Similar results were found using light transmittance aggregometry with 5 µM adenosine diphosphate, VerifyNow P2Y(12), and vasodilator-stimulated phosphoprotein phosphorylation assays. CONCLUSIONS: For patients receiving maintenance clopidogrel therapy after an ACS event, switching from clopidogrel to prasugrel is associated with a further reduction in platelet function by 1 week using prasugrel MD or within 2 h with the administration of a prasugrel LD. (A Pharmacodynamic Comparison of Prasugrel [LY640315] Versus Clopidogrel in Subjects With Acute Coronary Syndrome Who Are Receiving Clopidogrel [SWAP]; NCT00356135).


Asunto(s)
Síndrome Coronario Agudo/dietoterapia , Plaquetas/efectos de los fármacos , Piperazinas/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacocinética , Tiofenos/farmacocinética , Ticlopidina/análogos & derivados , Anciano , Angioplastia Coronaria con Balón , Clopidogrel , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piperazinas/administración & dosificación , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Clorhidrato de Prasugrel , Tiofenos/administración & dosificación , Ticlopidina/administración & dosificación , Ticlopidina/farmacocinética
5.
Coron Artery Dis ; 17(6): 493-9, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16905960

RESUMEN

OBJECTIVE: Erectile dysfunction and coronary artery disease share similar risk factors. Although phosphodiesterase-5 inhibitors used to treat erectile dysfunction do not adversely affect hemodynamic parameters in patients with coronary artery disease, their effects on myocardial blood flow are unknown. METHODS: In a randomized, double-blind, crossover study we examined the effects of tadalafil, 20 mg, compared with placebo on myocardial blood flow in patients with stable coronary artery disease (n=7, 52-73 years old). After tadalafil or placebo, myocardial blood flow was measured with positron emission tomography (nine-segment model) at rest, during maximal coronary hyperemia with adenosine, and during increased myocardial work with dobutamine. Abnormal flow was defined as myocardial blood flow <75% of maximum perfusion during adenosine plus placebo (46 normal/17 abnormal segments dentified). RESULTS: Compared with placebo, tadalafil had no significant effect on global myocardial blood flow at rest, during adenosine infusion, or during dobutamine infusion. Similarly, in normal and abnormal segments, tadalafil versus placebo had no significant effect on resting myocardial blood flow or on adenosine-induced increases in myocardial blood flow. In normal segments, myocardial blood flow with dobutamine plus tadalafil was greater than that with dobutamine plus placebo (1.79+/-0.56 versus 1.56+/-0.37 ml/g per min, P<0.01), and in abnormal segments, there was a trend for tadalafil compared with placebo to increase myocardial blood flow during dobutamine infusion (1.46+/-0.44 versus 1.36+/-0.36 ml/g per min, P=0.7). CONCLUSIONS: Tadalafil had no significant effect on global myocardial blood flow at rest, during adenosine infusion, or during dobutamine infusion. Compared with placebo, tadalafil significantly augmented myocardial blood flow during increased workload in normal regions, with a trend toward improving myocardial blood flow in poorly perfused regions.


Asunto(s)
Carbolinas/farmacología , Enfermedad de la Arteria Coronaria/fisiopatología , Circulación Coronaria/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Adenosina/administración & dosificación , Anciano , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Circulación Coronaria/fisiología , Estudios Cruzados , Dobutamina/administración & dosificación , Método Doble Ciego , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Cintigrafía , Tadalafilo
6.
J Sex Med ; 1(2): 201-8, 2004 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16422975

RESUMEN

INTRODUCTION: Tadalafil is a phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction (ED). Past clinical trials have assessed its efficacy and safety in western populations. Tadalafil has not been investigated in a large clinical trial with a South-east Asian population. AIM: To assess the efficacy and safety of on-demand tadalafil for the treatment of ED in a 12-week, double-blind, placebo-controlled study in Taiwan. METHODS: Men with mild to severe ED of various etiologies were randomized to receive placebo, tadalafil 10 mg, or tadalafil 20 mg, taken as needed (maximum once daily). Efficacy assessments included the International Index of Erectile Function, the Sexual Encounter Profile (SEP) diary, and a Global Assessment Question (GAQ). RESULTS: Tadalafil significantly improved erectile function compared with placebo (P < 0.005, all measures). At endpoint, the patients receiving tadalafil reported a greater mean per-patient percentage of successful intercourse attempts (SEP question 3: 70.0%, 10 mg; 78.0%, 20 mg) than placebo-treated patients (42.8%) and a greater proportion of improved erections (GAQ: 92.3% and 84.6% vs. 54.5%). Most treatment-emergent adverse events were mild or moderate. The most common adverse events were back pain, dyspepsia, and myalgia. CONCLUSIONS: Tadalafil was an effective, well-tolerated therapy for men in Taiwan with ED of broad-spectrum severity and etiology.


Asunto(s)
Carbolinas/uso terapéutico , Disfunción Eréctil/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Administración Oral , Anciano , Dolor de Espalda/inducido químicamente , Carbolinas/administración & dosificación , Carbolinas/efectos adversos , Método Doble Ciego , Dispepsia/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/efectos adversos , Placebos , Tadalafilo , Taiwán , Resultado del Tratamiento
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