Background The aim of this study was to compare rate of onset, magnitude, and consistency of platelet inhibition after administration of prasugrel or clopidogrel and to relate platelet inhibition to ...systemic exposure to each active metabolite. Thienopyridines are prodrugs, metabolized in vivo to active metabolites that inhibit the platelet P2Y12 adenosine diphosphate (ADP) receptor. Methods This was an open-label, 2-way, crossover study that randomized healthy subjects (n = 68) to an oral loading dose (LD) of prasugrel 60 mg or clopidogrel 300 mg. Platelet aggregation response to 5 and 20 μmol/L of ADP was measured by turbidometric aggregometry. Plasma concentrations of the active metabolites of prasugrel and clopidogrel were quantified by liquid chromatography with tandem mass spectrometry detection methods. Results Inhibition of platelet aggregation (IPA) after prasugrel was significantly higher ( P < .01) than that after clopidogrel from 15 minutes through 24 hours (5 μmol/L ADP) and from 30 minutes through 24 hours (20 μmol/L ADP). For 20 μmol/L ADP, the median time to reach ≥20% IPA was 30 minutes for prasugrel and 1.5 hours for clopidogrel ( P < .001). The maximum IPA was 84.1% ± 9.5% with prasugrel versus 48.9% ± 27.0% with clopidogrel for 5 μmol/L ADP and 78.8% ± 9.2% versus 35.0% ± 24.5%, respectively, for 20 μmol/L ADP ( P < .001). Response to prasugrel was more consistent compared to clopidogrel ( P < .01). The lower IPA response to clopidogrel was associated with lower plasma concentrations of its active metabolite ( P < .001). Conclusions Prasugrel 60 mg LD results in more rapid, potent, and consistent inhibition of platelet function than clopidogrel 300 mg LD. Lower IPA responses to clopidogrel were associated with lower concentrations of its active metabolite.
Abstract Background: Prasugrel is an oral antiplatelet agent approved for the reduction of atherothrombotic cardiovascular events in patients presenting with acute coronary syndrome and undergoing ...percutaneous coronary intervention. Although the approved loading dose is 60 mg, earlier studies of prasugrel suggested that active-metabolite exposure and pharmacodynamic response may be higher in Asian subjects than in white subjects. Objectives: This study compared the pharmacodynamic response to a single 30-mg dose of prasugrel in healthy Chinese and white subjects and the response to a single 30-mg dose of prasugrel and a single 300-mg dose of clopidogrel in healthy Chinese subjects. The pharmacokinetics and tolerability of both drugs were also assessed. Methods: This was an open-label, single-dose study conducted in Singapore. Chinese subjects were randomly allocated to receive prasugrel 30 mg or clopidogrel 300 mg; after a 14-day washout period, they received the alternative drug. White subjects received only prasugrel 30 mg. Blood samples for pharmaco-dynamic assessments were collected before dosing and at 0.5, 1, 2, 4, and 24 hours after dosing. Three methods were used to measure inhibition of platelet aggregation (IPA)—traditional light transmission aggregometry (LTA), the Verify Now P2Y12 (VN-P2Y12) assay, and a vasodilator-stimulated phosphoprotein (VASP) phosphorylation flow cytometry assay—and their results were compared. Blood samples for pharmacokinetic assessments were collected at 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, and 24 hours after dosing. Concentrations of the active metabolite of prasugrel were measured using a validated LC-MS/MS method. Results: The study enrolled 18 Chinese subjects and 14 white subjects. Chinese subjects had a mean (SD) age of 31 (10) years and a mean body weight of 65.2 (8.9) kg; 83% were male. The corresponding values for white subjects were 30 (10) years, 77.2 (12.4) kg, and 86%. Thirty of the 32 enrolled subjects completed the study. Two Chinese men were withdrawn from the study, one due to a low platelet-rich plasma count after receipt of prasugrel 30 mg and the other due to mild, intermittent rectal bleeding after bowel movements that began ∼2 days after receipt of clopidogrel 300 mg. The mean IPA with prasugrel was significantly higher in Chinese than in white subjects at 0.5, 1, and 2 hours after dosing ( P < 0.05), but not at 4 or 24 hours. In Chinese subjects, mean maximal IPA (87%) occurred 1 hour after prasugrel dosing; in white subjects, mean maximal IPA (78%) occurred 2 hours after prasugrel dosing. In Chinese subjects, the mean IPA was significantly higher at all time points after administration of prasugrel 30 mg than after administration of clopidogrel 300 mg ( P <0.001). After administration of Clopidogrel 300 mg in Chinese subjects, mean maximal IPA (58%) occurred at 4 hours. The VN-P2Y12 and VASP phospho-rylation assays yielded results comparable to those obtained by LTA. Mean exposure to prasugrel's active metabolite was higher in Chinese than in white subjects (geometric least squares mean ratio for AUC0−t = 1.47 (90% CI, 1.24–1.73). Both drugs were well tolerated. Conclusions: In this study, platelet inhibition was significantly higher in Chinese than in white subjects up to 2 hours after a single 30-mg dose of prasugrel. Platelet inhibition was significantly higher in Chinese subjects at all time points after a 30-mg dose of prasugrel than after a 300-mg dose of clopidogrel. Both treatments were generally well tolerated.
Failure to achieve an adequate level of platelet inhibition during percutaneous coronary intervention is associated with an increased risk for periprocedural myocardial injury. This study was ...conducted to compare the initial rate of platelet inhibition after a loading dose (LD) of prasugrel or clopidogrel and determine the association between the initial rate of inhibition and pharmacodynamic responder status. Data were pooled from 3 studies in which healthy subjects received LDs of prasugrel (60 mg; n = 76) or clopidogrel (300 mg; n = 87). Maximum platelet aggregation (MPA; 20 μmol/L adenosine diphosphate) was measured by turbidimetric aggregometry (0.25 to 24 hours after dosing). A mechanistic model was used to estimate the initial rate of decrease in MPA per hour (fast onset: MPA decrease >20%/hour). Subjects were defined as pharmacodynamic poor responders if the absolute decrease in MPA from baseline was <15% at either 4 to 5 or 24 hours after dosing. The median initial rate of decrease in MPA was greater after prasugrel (203%/hour) than with clopidogrel (23%/hour) (p <0.001). Overall, 76 subjects (100%) receiving prasugrel had fast onset of platelet inhibition compared with 47 subjects (54%) receiving clopidogrel. The initial rate of decrease in MPA was highly correlated with responder status (p <0.001). After prasugrel, subjects had a lower median MPA compared with clopidogrel (p <0.001; from >0.25 to 24 hours after dosing), and intersubject variability in MPA response was less after prasugrel compared with clopidogrel (p <0.001; from >1 to 24 hours after dosing). In conclusion, platelet inhibition after a 60-mg LD of prasugrel was more rapid in onset, less variable, and greater in magnitude than with a 300-mg LD of clopidogrel. After a thienopyridine LD, the initial rate of platelet inhibition was predictive of pharmacodynamic responder status.
Objective The study objective was to evaluate risk factors for poor weight gain in infants with hypoplastic left heart syndrome after stage 1 palliation. Methods We reviewed all term infants with ...hypoplastic left heart syndrome who had stage 1 palliation and stage 2 palliation at Texas Children's Hospital between 2000 and 2011 (n = 120). Predictor variables included age at stage 1 palliation, intensive care unit factors, calories delivered, and echocardiographic findings. Outcome variables included weight for age Z scores at hospital discharge, stage 2 palliation, and change in weight for age Z scores between stage 1 palliation and hospital discharge. Results Complete nutritional data were available for 47 of 120 patients. Median total parenteral nutrition duration was 6 days (range, 1-43 days), and median intensive care unit calories delivered was 53.9 kcal/kg/d (range, 22.3-119.6 kcal/kg/d). Before hospital discharge, the median caloric intake was 106.7 kcal/kg/d (range, 70.0-152.0 kcal/kg/d). Median weight for age Z scores was −0.59 (range, −3.6 to 0.5) at stage 1 palliation, −1.62 (range, −4.5 to −0.1) at intensive care unit transfer, and −1.81 (range, −4.9 to −0.5) at hospital discharge. A total of 46 of 47 patients had a negative change in weight for age Z scores between stage 1 palliation and hospital discharge, with a median change of −1.14 (range, −2.3 to 0.6). Change in weight for age Z scores from stage 1 palliation to discharge was directly associated with calories delivered and indirectly associated with hospital length of stay and moderate tricuspid regurgitation ( P < .001). Conclusions Postoperative nutrition fails to meet the needs of infants with hypoplastic left heart syndrome despite increased focus on nutritional support. Modifiable factors (eg, nutritional intake) and hemodynamic factors (eg, tricuspid regurgitation) may play roles in the poor weight gain of these infants.
Magnetic resonance imaging (MRI) allows visualization of location and extent of radiofrequency (RF) ablation lesion, myocardial scar formation, and real-time (RT) assessment of lesion formation. In ...this study, we report a novel 3-Tesla RT -RI based porcine RF ablation model and visualization of lesion formation in the atrium during RF energy delivery.
The purpose of this study was to develop a 3-Tesla RT MRI-based catheter ablation and lesion visualization system.
RF energy was delivered to six pigs under RT MRI guidance. A novel MRI-compatible mapping and ablation catheter was used. Under RT MRI, this catheter was safely guided and positioned within either the left or right atrium. Unipolar and bipolar electrograms were recorded. The catheter tip-tissue interface was visualized with a T1-weighted gradient echo sequence. RF energy was then delivered in a power-controlled fashion. Myocardial changes and lesion formation were visualized with a T2-weighted (T2W) half Fourier acquisition with single-shot turbo spin echo (HASTE) sequence during ablation.
RT visualization of lesion formation was achieved in 30% of the ablations performed. In the other cases, either the lesion was formed outside the imaged region (25%) or the lesion was not created (45%) presumably due to poor tissue-catheter tip contact. The presence of lesions was confirmed by late gadolinium enhancement MRI and macroscopic tissue examination.
MRI-compatible catheters can be navigated and RF energy safely delivered under 3-Tesla RT MRI guidance. Recording electrograms during RT imaging also is feasible. RT visualization of lesion as it forms during RF energy delivery is possible and was demonstrated using T2W HASTE imaging.
Objective To describe the prevalence, characteristics, and predictors of electrographic seizures after convulsive status epilepticus (CSE). Study design This was a multicenter retrospective study in ...which we describe clinical and electroencephalographic (EEG) features of children (1 month to 21 years) with CSE who underwent continuous EEG monitoring. Results Ninety-eight children (53 males) with CSE (median age of 5 years) underwent subsequent continuous EEG monitoring after CSE. Electrographic seizures (with or without clinical correlate) were identified in 32 subjects (33%). Eleven subjects (34.4%) had electrographic-only seizures, 17 subjects (53.1%) had electroclinical seizures, and 4 subjects (12.5%) had an unknown clinical correlate. Of the 32 subjects with electrographic seizures, 15 subjects (46.9%) had electrographic status epilepticus. Factors associated with the occurrence of electrographic seizures after CSE were a previous diagnosis of epilepsy ( P = .029) and the presence of interictal epileptiform discharges ( P < .0005). The median (p25 -p75 ) duration of stay in the pediatric intensive care unit was longer for children with electrographic seizures than for children without electrographic seizures (9.5 3-22.5 vs 2 2-5 days, Wilcoxon test, Z = 3.916, P = .0001). Four children (4.1%) died before leaving the hospital, and we could not identify a relationship between death and the presence or absence of electrographic seizures. Conclusions After CSE, one-third of children who underwent EEG monitoring experienced electrographic seizures, and among these, one-third experienced entirely electrographic-only seizures. A previous diagnosis of epilepsy and the presence of interictal epileptiform discharges were risk factors for electrographic seizures.
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