Dose Of Prasugrel Research Articles

Thrombozytenaggregationshemmer: Was sind die Risiken?

The most common risks related to platelet inhibitor therapy are bleeding, drug-drug interactions and therapeutic failure. The new substances prasugrel and ticagrelor are more potent platelet inhibitiors than clopidogrel. This reduces the incidence of ischemic events, but also potentially increases the bleeding risk. Clopidogrel therapy has up to 20% non-response rates, which can partially be explained by genetic polymorphisms and drug-drug interactions. Currently no evidence exists that ticagrelor or prasugrel efficacy is affected by genetic polymorphisms. The therapy in patients at risk still has to be carefully adapted to minimize adverse events. Patients older than 75 years and/or weighing less than 60 kg should receive a reduced dose of prasugrel. The combination of ticagrelor with strong cytochrome-P450-3A4 inhibitors is contraindicated.

Randomized comparison of the platelet inhibitory efficacy between low dose prasugrel and standard dose clopidogrel in patients receiving dual antiplatelet therapy after coronary stent implantation

Randomized comparison of the platelet inhibitory efficacy between low dose prasugrel and standard dose clopidogrel in patients receiving dual antiplatelet therapy after coronary stent implantation

GW24-e2375 Onset of antiplatelet effect of prasugrel and ticagrelor is delayed in patients with acute coronary syndromes

ObjectivesA more rapid onset of antiplatelet effect following loading with prasugrel and ticagrelor compared to clopidogrel was demonstrated for healthy subjects and patients with stable coronary artery disease. These results...

ARCTIC: Additional proof against antiplatelet adjusted therapy

[first paragraph of article] The prognostic value of high platelet reactivity during treatment with aspirin and/or thienopyridine has been demonstrated repeatedly, leading to the rationale for individualized antiplatelet therapy. Bedside tests have previously been used as screening tools to select patients with a poor response to clopidogrel in order to evaluate different treatments. However, conflicting results of such interventions have been reported in cohort studies and randomized studies. In randomized studies, the intensification of platelet inhibition in patients with a poor response to clopidogrel failed to improve outcomes when double doses of clopidogrel or prasugrel were used, whereas glycoprotein IIb/IIIa inhibition improved outcomes in these patients.

Differential Effect of Ticagrelor Versus Prasugrel on Coronary Blood Flow Velocity in Patients With Non–ST-Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

Prasugrel and ticagrelor provide a superior anti-ischemic action than clopidogrel, with some of ticagrelor's benefits possibly attributed to adenosine-mediated mechanisms. We aimed to compare the effect of maintenance dose of ticagrelor versus prasugrel on coronary blood flow velocity (CBFV) during increasing doses of intravenously administered adenosine. In a prospective, single-center, single-blind, crossover study, 56 patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention were randomized to receive either ticagrelor 90 mg BID or prasugrel 10 mg OD with a 15-day treatment period. At the end of each treatment period, CBFV by transthoracic Doppler echocardiography was assessed at baseline and under incremental doses (50 μg/kg per minute, 80 μg/kg per minute, 110 μg/kg per minute, and 140 μg/kg per minute) of adenosine infusion. Maximal CBFV area under the curve was higher for ticagrelor-treated than for prasugrel-treated patients, with a least squares mean difference of 7.16 (95% confidence interval, 2.61-11.7; P=0.003). Maximal CBFV/baseline CBFV ratio was higher with ticagrelor than prasugrel at 50, 80, and 110 μg/kg per minute but not at 140 μg/kg per minute adenosine infusion rate, with mean difference (95% confidence interval) of 0.17 (0.08-0.26; P<0.001), 0.21 (0.02-0.41; P=0.03), 0.24 (0.01-0.47; P=0.04), and 0.14 (-0.12 to 0.4; P=0.3), respectively. In patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention, ticagrelor augments CBFV to a greater extent than prasugrel when incremental doses of adenosine are administered. Although exploratory, these results may represent a pleiotropic action of ticagrelor, possibly contributing to its beneficial effects in such patients.

A phase 1 study of prasugrel in patients with sickle cell disease: pharmacokinetics and effects on ex vivo platelet reactivity

AimsPrasugrel 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.MethodsThirteen 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.ResultsAt 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 &lt; 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.ConclusionsResults 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.

Antiplatelet Therapy and Cardiac Surgery: Review of Recent Evidence and Clinical Implications

Since the publication of the 2009 Canadian Cardiovascular Society position paper on antiplatelet therapy and cardiac surgery, new antiplatelet strategies with either double-dose clopidogrel or with new and more potent agents (prasugrel and ticagrelor) have become accepted practice. For the patient requiring coronary artery bypass surgery who has recently received either double-dose clopidogrel or one of the new P2Y12 platelet inhibitors, increased perioperative bleeding can be anticipated. For patients who are stable and can wait, surgery should be delayed for 5 days after the last dose of clopidogrel (standard or double-dose), and for 7 days after the last dose of prasugrel. Patients who have received ticagrelor should wait 5 days after the last dose before surgery, although it is likely that surgery can be safely performed 3 days after discontinuing ticagrelor. For patients who require emergency surgery despite recently receiving double-dose clopidogrel, prasugrel, or ticagrelor, the measures to limit perioperative bleeding discussed in the 2009 Canadian Cardiovascular Society position paper remain applicable, but have not yet been rigourously tested. Recent studies have suggested the value of preoperative in vitro platelet aggregometry to determine perioperative bleeding risk.

Traitement préhospitalier par bivalirudine de l’infarctus aigu du myocarde orienté vers une angioplastie primaire. À propos d’une série consécutive de 152 cas

Objective of the studyBivalirudin, a direct thrombin inhibitor, demonstrated an improvement in the prognosis of acute coronary syndromes by a decrease in major bleeding complications. This observational study evaluated inhospital outcome of patients with acute myocardial infarction treated by prehospital bivalirudin before primary angioplasty. Patients and methodsWe included, from June 2010 to June 2012, all patients with acute myocardial infarction receiving prehospital bivalirudin with bolus of 0.75mg/kg followed by an infusion of 1.75mg/kg per hour until the arrival in the catheterization laboratory. Bivalirudin was possibly continued after primary angioplasty. ResultsWe included 152 patients aged 57.6±11.6 years. A prehospital 60mg loading dose of prasugrel was given in 77% of patients. Coronary angiography with radial access (77.6%) was performed before a successful angioplasty in 97.3% of cases. The bivalirudin infusion was continued after the procedure in 81.6% of patients. Inhospital outcome showed two deaths (1.3%) and two re-infarctions (1.3%) of which one was related to the single acute stent thrombosis (0.6%). Major bleeding complications were limited irrespective of the Gusto (0.6%), Timi (0.6%) or Horizons-MI (4.6%) classification. Bleeding complications rate was similar when bivalirudin was followed or not after primary angioplasty. ConclusionThe use of bivalirudin in the prehospital setting for primary angioplasty seems to be effective and safe about ischemic and bleeding complications during the inhospital outcome.

Letter by Grove and Kristensen Regarding Article, “Randomized Assessment of Ticagrelor Versus Prasugrel Antiplatelet Effects in Patients With ST-segment–elevation Myocardial Infarction”

To the Editor: We have read with interest the recent article regarding insufficient effect of oral antiplatelet drugs in the acute phase of ST-segment– elevation myocardial infarction (STEMI).1 Alexopoulos et al1 evaluated platelet inhibition at 0, 1, 2, 6, 24 hours, and 5 days in patients with STEMI, undergoing primary percutaneous coronary intervention. All patients were treated with heparin and aspirin and were randomized to standard loading and maintenance doses of either ticagrelor or prasugrel. The authors reported a high frequency of high on-treatment platelet reactivity at the first 3 time …

Abstract WMP25: Single-Center Experience with Dual Antiplatelet Therapy Management in Patients Treated with the Pipeline Embolization Device

Purpose: To determine the number of clopidogrel or prasugrel dose adjustments needed and final DAT regimen used to maintain patients undergoing Pipeline Embolization Device (PED) procedures within a target P2Y12 inhibition range. Methods: We recorded the number of clopidogrel or prasugrel dose adjustments, final DAT regimen and thromboembolic and hemorrhagic complications in patients undergoing PED procedures at our institution over an 8-month period. P2Y12 inhibition was measured with VerifyNow 10 and 30 days after dose adjustments (target range 80-200 P2Y12 reaction units). Patients received 325mg aspirin daily. Results: Forty-four patients underwent PED procedures at our institution during the study period, 36 female and 8 male, mean age 59 years (median 63 years, range 31-81 years). Thirteen patients did not require dose adjustments to remain within the target P2Y12 inhibition range (30%). Thirty-one patients required dose adjustments to remain within the target P2Y12 inhibition range (70%), with a mean of 2.1 dose adjustments per patient (median 2, range 1-5), and a mean time from initiation of DAT to last dose adjustment of 47.5 days (median 42 days, range 8-149 days). Four patients exceeded the target P2Y12 inhibition range after a dose adjustment (13%, 3 prasugrel, 1 clopidogrel), without complications. The table summarizes the final DAT regimen and associated major thromboembolic and hemorrhagic complications leading to death or a permanent neurological deficit in our cohort. Most major complications (80%) occurred in patients who were outside the target P2Y12 inhibition range shortly before or at the time of the complication. Conclusion: The majority of patients undergoing PED procedures in our cohort (70%) required an average of 2 clopidogrel or prasugrel dose adjustments to remain within a target P2Y12 inhibition range. Future research is needed to determine if active management of DAT may decrease the risk of major complications after PED procedures.

Pharmacodynamic Comparisons for Single Loading Doses of Prasugrel (30mg) and Clopidogrel (600mg) in Healthy Korean Volunteers

Previous studies involving a loading dose (LD) of 60 mg prasugrel have suggested that active metabolite exposure and pharmacodynamic responses may be higher in persons of Asian ethnicity than in Caucasian subjects. The aim of this study was to determine the pharmacodynamic effect of an LD of 30 mg prasugrel and 600 mg clopidogrel in healthy Korean volunteers. Twelve volunteers were randomly assigned to a prasugrel or a clopidogrel group. Following a 2-week washout period, group designations and treatments were switched (6 per group). Platelet function was serially measured via light transmission aggregometry (LTA), VerifyNow and multiple electrode platelet aggregometry (MEA) assays at baseline and 0.5, 2, 6, and 24h after LD. Inhibition of platelet aggregation (IPA) at 0.5-24 h after prasugrel was significantly higher (P<0.001) than that achieved by clopidogrel. The prasugrel peak IPA at 2 h after LD was 93.7% (±6.2%) compared to the clopidogrel peak IPA at 6h after LD at 65.8% (±17.2%). The VerifyNow and MEA assay yielded results similar to those obtained by LTA. In healthy Korean subjects, a 30-mg LD of prasugrel yields a more rapid, potent and consistent inhibition of platelet function than a 600-mg LD of clopidogrel.

Comparison of antiplatelet effects of prasugrel and ticagrelor in cynomolgus monkeys by an ELISA-based VASP phosphorylation assay and platelet aggregation

Prasugrel is the third generation thienopyridine prodrug, and ticagrelor is a non-competitive direct acting P2Y12 antagonist. In phase 3 studies, both agents reduced ischaemic event rates compared to clopidogrel. The present in vitro human and monkey studies showed that ticagrelor's active metabolite (AM) was more potent than ticagrelor and prasugrel's AM on inhibition of ADP-induced platelet aggregation by light transmission aggregometry and ELISA-based vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay. In contrast, on an oral dosage basis (mg/kg), prasugrel showed more potent platelet inhibition compared to ticagrelor on ex vivo aggregation and VASP phosphorylation assays in monkeys. Single oral doses of prasugrel (0.3 and 1 mg/kg) resulted in robust antiplatelet effects, which were sustained up to 24 hours after administration. Ticagrelor (3 and 10 mg/kg, p.o.) also showed significant antiplatelet effects but its effects were diminished at 24 hours after the dosing. Repeat administration of prasugrel (1.8 mg/kg loading dose [LD], 0.3 mg/kg once daily maintenance dose [MD]) showed more rapid antiplatelet effects and longer duration of action throughout the entire day. Twice a day repeat administration of ticagrelor (10 mg/kg bid MD following a single 20 mg/kg LD) also showed significant antiplatelet effects but with more intra-day variability compared to prasugrel. The in vitro and ex vivo studies showed strong correlations between platelet aggregation and VASP phosphorylation for prasugrel, ticagrelor and their AMs. These strong correlations between platelet aggregation and VASP phosphorylation in non-human primates also suggest that ELISA-based human VASP assay can be utilised for non-human primate platelet studies.

Safety of Reloading Prasugrel in Addition to Clopidogrel Loading in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

Patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI) commonly receive a loading dose of either clopidogrel or prasugrel, in addition to aspirin. The present study aimed to assess the safety of reloading prasugrel in patients who had initially received a loading dose of clopidogrel compared to prasugrel loading alone. The study included a cohort of 606 consecutive patients with acute coronary syndrome who had received a 60-mg loading dose of prasugrel before PCI. These patients were then categorized into clopidogrel preloading (300 or 600 mg) followed by prasugrel reloading (CP-load group, n = 90) and prasugrel loading only (P-load group, n = 516). Both groups received a 10-mg maintenance dose of prasugrel after PCI. The primary end point was in-hospital Thrombolysis In Myocardial Infarction-defined major bleeding. The secondary end points were other in-hospital bleeding complications and major cardiovascular events. Patients in the CP-load group compared to the P-load group were younger, with lower rates of cardiovascular risk factors. Significantly more patients in the CP-load group presented with biomarker-positive myocardial infarction (80.0% vs 30.6%, p ≤0.001) and cardiogenic shock (5.6% vs 1.4%, p = 0.022). No significant differences (p = NS) were seen in Thrombolysis In Myocardial Infarction major bleeding (2.6% vs 2.8%), Thrombolysis In Myocardial Infarction major or minor bleeding (12.2% vs 7.0%), the need for blood transfusion (2.6% vs 2.1%), and vascular complications (1.3% vs 2.0%) between groups. The CP-load group experienced more in-hospital major adverse cardiac events (5.6% vs 1.6%, p = 0.031), urgent coronary artery bypass grafting (3.3% vs 0.2%, p = 0.011), and longer hospital and intensive care unit stays. In conclusion, preloading with clopidogrel should not be prohibitive to reloading with prasugrel in patients presenting with acute coronary syndrome and undergoing PCI with respect to bleeding and vascular complications.

Use of Eptifibatide as a Bridge Antiplatelet Agent for Intrathecal Drug Delivery System Placement

Use of antiplatelet agents is becoming increasingly common, and their management may require new strategies if neuroaxial techniques are to be employed in patients who will not tolerate discontinuation of antiplatelet therapy. The patient was a 46-year-old man with a past medical history significant for coronary artery disease and who had undergone 14 stents. He developed stent thrombosis (ST) while on clopidogrel. Following the ST, he was subsequently placed on prasugrel. While on prasugrel, the patient presented for an intrathecal drug delivery system (IDDS) trial and placement due to severe peripheral neuropathy unresponsive to several conservative medical treatments. He had previously undergone an unsuccessful spinal cord stimulator trial and received no pain relief. In consultation with his outside cardiologist, the patient received permission to hold his prasugrel for 7 days prior to his intrathecal pump trial. During the trial period’s inpatient hospitalization, the patient developed chest pain. In consultation with the cardiology service in our institution, it was decided antiplatelet therapy should be re-instituted. The patient was bridged to his IDDS placement after the trial with intravenous eptifibatide. The eptifibatide drip was administered 6 hours prior to the IDDS implant. Functional platelet count was checked one hour before the IDDS was placed and the pump was placed without incident. The eptifibatide drip was reinstituted one hour after the IDDS implantation. The patient was observed for 24 hours on the eptifibatide drip, transitioned to his home dose of prasugrel, and discharged home. At outpatient follow-up one week later, the patient demonstrated no neurologic or hemorrhagic complications and was satisfied with the pain control provided by the IDDS. Prasugrel is an irreversible platelet inhibitor, which prevents ADP-induced platelet aggregation by binding the P2Y12 receptor. Patients taking prasugrel will have deficient platelet activity until new platelets have been produced, a span of approximately 7 days. Eptifibatide is an intravenous glycoprotein IIb/IIIa inhibitor with a short half-life of 2½ hours. Inhibition of glycoprotein IIb/IIIa prevents platelet activation and aggregation. The drug effect ceases once it is discontinued and restoration of platelet function is not dependent upon new platelet production. Patients requiring antiplatelet therapy in need of neuroaxial pain management procedures present challenging problems to pain management physicians. Current guidelines from the American Society of Regional Anesthesia have not identified any bridging agent suitable for patients who may not tolerate prolonged withdrawal from their antiplatelet therapy. In this case, eptifibatide was successfully utilized to bridge a patient whose comorbid conditions necessitated continuous antiplatelet therapy without the prolonged washout common to irreversible antiplatelet agents. Key words: Intrathecal drug delivery system, anticoagulation, pain, eptifibatide, antiplatelet agents.

Clopidogrel pretreatment of patients with ST-elevation myocardial infarction does not affect platelet reactivity after subsequent prasugrel-loading: Platelet reactivity in an observational study

Current guidelines recommend prasugrel or ticagrelor for patients undergoing percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI). Whereas available data support ticagrelor independent of pretreatment with clopidogrel, corresponding data for prasugrel are missing. Here, we investigated platelet reactivity after loading with prasugrel in clopidogrel-naïve vs. clopidogrel-pretreated patients. Forty-seven consecutive patients with STEMI referred for primary PCI were enrolled. Use of GPIIb/IIIa inhibitors and known contraindications to prasugrel served as exclusion criteria. A total of 31 patients were already treated with a loading dose of clopidogrel 600 mg by the emergency medical system before admission, while 16 patients were P2Y12 antagonist naïve. All patients received a loading dose of prasugrel 60 mg immediately before PCI. Adenosine diphosphate (ADP) induced platelet reactivity was determined by VerifyNow™ P2Y12 assay, by light transmission aggregometry (LTA) and by multiple electrode impedance aggregometry (MEIA; Multiplate™ analyser). No differences in platelet reactivity were observed at day 1 after PCI between the bolus-on-bolus treatment regimen and single prasugrel loading. Platelet reactivity was profoundly decreased to 10 [8–31] platelet reactivity unit (PRU; median [interquartile range]) in patients on clopidogrel + prasugrel vs. 9 [6–60] PRU in patients on prasugrel only (p = 0.916). Consistent results were obtained by LTA and MEIA. The proportion of patients reaching a MEIA associated with increased risk bleeding (<188 AU*min) was also similar between the two study groups. The level of platelet reactivity at day 1 after the 60 mg loading dose of prasugrel was independent of pretreatment with clopidogrel. Our results do not support withholding prasugrel in patients pretreated with clopidogrel who undergo PCI for STEMI.

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Introduction: There are limited pharmacokinetic data and no clinical data on how to transition patients from clopidogrel to prasugrel, a more potent thienopyridine, as patients receiving a clopidogrel within the previous 5 days were excluded from the major clinical trial supporting prasugrel for the treatment of acute coronary syndromes (ACS) treated with percutaneous intervention (PCI). Adequate platelet inhibition is important in treating ACS to prevent thrombotic complications. The purpose of this study is to describe the safety of a loading dose of prasugrel in patients switching from clopidogrel for the treatment of ACS. Hypothesis: The hypothesis was that loading a patient with prasugrel after receiving clopidogrel is safe when treating ACS. Methods: Patients treated with a loading dose of prasugrel for ACS between Jan 2010 and July 2012 were retrospectively identified. Patients were included if they received clopidogrel within the previous 48 hours. Primary outcome was the development of TIMI major bleeding at 30 days or during index hospitalization. Results: 28 patients met inclusion criteria; 19 patients (68%) received a clopidogrel loading dose (300-600mg) prior to prasugrel loading, 9 (32%) were on maintenance clopidogrel therapy (75mg). Baseline characteristics were: average age 53 years (range 32-73 yrs); 86% male; 75% Caucasian; 32% diabetes; 57% admission diagnosis of STEMI; 86% required ICU admission after PCI; average weight 88.6 kg (range 66-108 kg). Of the patients who received a clopidogrel load prior to prasugrel, 58% received 300mg and prasugrel was started 19 hrs later on average; patients not receiving a clopidogrel load had prasugrel started 10 hrs after the last dose of clopidogrel. All but 1 patient were treated with PCI; 67% received a drug eluting stent (DES). The patient not treated with PCI had recent DES placed, developed an allergic reaction to clopidogrel and subsequently developed stent thrombosis; the patient underwent thrombus aspiration without PCI and was switched to prasugrel. No patient developed TIMI major bleeding. Overt bleeding was not observed in any patient but 1 patient required transfusion of 2 units of packed red blood cells. No patient died during the hospital stay and the average length of stay was 3.6 days. Conclusions: Loading a patient with prasugrel even if the patient has already received clopidogrel appears to have an adequate safety profile. This could be a favorable strategy in high risk patients when more potent antiplatelet therapy may be preferred. Larger studies would be needed to verify these safety results given the potent nature of prasugrel.

Prasugrel in Children with Sickle Cell Disease: Pharmacokinetic and Pharmacodynamic Characteristics from an Open-Label, Adaptive-Design, Dose-Ranging Study

Abstract 3213 Introduction:There are few approved treatments for children with sickle cell disease (SCD) who experience painful vaso-occlusive crises (VOC). Evidence suggests a pathophysiologic role for platelets in SCD, in general, and in VOC, specifically. Thrombocytosis is common, and markers of platelet activation, are elevated in both children and adults with SCD. This activation may be mediated by adenosine diphosphate (ADP) released from hemolysis of sickled erythrocytes. Accordingly, platelets are a rational therapeutic target to explore with the aim to reduce the frequency and severity of VOC. Therefore, we studied prasugrel, an irreversible P2Y12 ADP receptor antagonist that inhibits platelet activation and aggregation, in children with SCD. The primary objective was to identify doses of prasugrel that produced a 30–50% inhibition of platelet activation for use in a pediatric phase 3 study of efficacy. Methods:We conducted a phase 2, open-label, multi-center, adaptive-design, dose-ranging, pharmacokinetic (PK) and pharmacodynamic (PD) study of prasugrel in children with SCD. Males and females 2–17 years of age (inclusive) with SCD (HbSS and HbSβ0-thalassemia genotypes) were eligible. Treatment was initiated with single prasugrel doses expected to have no effect and dosage was increased in accordance with an adaptive design for improved safety and dosage identification. Patients were to receive up to 3 single doses of prasugrel with the second and third doses being administered 14±4 days after the previous dose. Doses of prasugrel were increased or decreased based on the PD response to previous doses in the same patient and/or other patients. Demographic characteristics were also considered for dose assignment in order to balance age, body weight, and sex across the dose range that produced a 30–50% inhibition of platelet aggregation.Platelet inhibition was evaluated by the VerifyNow™ (VN) P2Y12 assay and the vasodilator-associated simulated phosphoprotein (VASP) phosphorylation assay. These PD measures were assessed at screening and 4 hours after each single prasugrel dose. Venous blood samples were collected 0.5 h, 1 h, 1.5 h, 2 h, and 4 h post-dose for PK analysis of prasugrel’s active metabolite to calculate the area under the concentration-time curve (AUC). The PK/PD analyses were conducted to describe the relationship between prasugrel’s active metabolite AUC and platelet inhibition. Spearman correlation statistics were used to assess the relationship between dose and PD parameters. Results:A total of 24 patients, ranging in age from 4 to 17 years of age, received at least one dose of prasugrel. The mean age was 11.0 years; 58.3% were female; 87.5% had HbSS and 12.5% had HbSβ0-thalassemia. Body weight ranged from 14.4 to 80.1 kg. Patients received single doses of prasugrel ranging from 0.03 to 0.60 mg/kg. A single-dose range of 0.30–0.50 mg/kg produced mean 30–50% inhibition in platelet activation by the VN assay whereas a single-dose range of 0.40–0.50 mg/kg produced mean 30–50% inhibition in the VASP assay. Minimal PD response was observed at single doses, up to approximately 0.25 mg/kg. Above 0.25 mg/kg, PD response increased with dose. The single 0.60 mg/kg dose produced >50% inhibition by both VN and VASP assays.In general, higher doses resulted in increased exposure to prasugrel's active metabolite. Increased variability in exposure and in PD response was seen at higher doses. The PD results demonstrate correlation between dose and 4-hour VN P2Y12 percent inhibition. Prasugrel appeared to be safe and well tolerated in this small patient sample. Three serious adverse events occurred in 2 patients; none of which were considered possibly related to prasugrel. No hemorrhagic events were observed, and no subjects discontinued participation due to an adverse event. Conclusions:These single-dose data will contribute to a population modeling strategy that targets the desired steady state range of platelet inhibition (30–50%) for a subsequent phase 3 clinical trial of the efficacy and safety of prasugrel for the reduction of VOC in children with SCD. Daily maintenance doses will be evaluated in a subsequent part of the current study. Disclosures:Styles:Eli Lilly and Company: Consultancy. Off Label Use: Inhibition of platelet activation by prasugrel in pediatric patients with sickle cell disease. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Heiselman:Eli Lilly and Company: Employment, Equity Ownership. Heath:Eli Lilly and Company: Employment, Equity Ownership. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Heeney:Novartis: Consultancy, Research Funding; Eli Lilly and Company: Research Funding; Pfizer: Consultancy. Redding-Lallinger:Eli Lilly and Company: Research Funding. Small:Eli Lilly and Company: Employment, Equity Ownership. Moser:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership.

Pharmacokinetics and pharmacodynamics of single and multiple doses of prasugrel in healthy native Chinese subjects

To characterize the pharmacokinetics (PKs), pharmacodynamics (PDs), and tolerability of different dose regimens of prasugrel in healthy Chinese subjects. This was a single-centered, open-label, parallel-design study. Subjects received a single loading dose (LD) of prasugrel followed by once-daily maintenance dose (MD) for 10 d. They were enrolled into 3 groups: 60 mg LD/10 mg MD; 30 mg LD/7.5 mg MD; 30 mg LD/5 mg MD. Blood samples were collected after the first and last dose. The serum concentration of the active metabolite of prasugrel was determined using a LC/MS/MS method. Platelet aggregation was assessed using the VerifyNow-P2Y(12) assay. Thirty-six healthy native Chinese subjects (19 males) aged 18-45 were enrolled; mean age and body weight were similar across the treatment groups (n=12 for each). The metabolite AUC(0-4) and C(max) increased dose-proportionally across the dose range of 5 mg to 60 mg. The median T(max) was 0.5 h in all groups. The PD parameters, indicated by the inhibition of ADP-induced platelet aggregation, were met more rapidly in the 60 mg group than the 30 mg group after the LD (94%-98%). This high degree of inhibition of platelet aggregation was maintained following the 10 mg MD (87%-90%) and was lower in the 7.5 mg and 5 mg MD groups (79%-83% and 64%-67%, respectively). Prasugrel was well tolerated in healthy Chinese subjects for single doses up to 60 mg and a MD of 10 mg for 10 d. The PKs and PDs of the active metabolite of prasugrel were similar to those in Chinese subjects reported by a previous bridging study, which demonstrated that the exposure to the active metabolite in Chinese subjects was higher than in Caucasians.

Residual platelet activation through protease-activated receptors (PAR)-1 and ‐4 in patients on P2Y12 inhibitors

BackgroundDual antiplatelet therapy with aspirin and thienopyridines has improved outcomes of patients after coronary stent implantation. However, current knowledge suggests that thrombin generation is not affected by inhibition of the P2Y12 receptor, and therefore, platelet activation may still occur. MethodsThe response to agonists specific for protease-activated receptors (PAR)-1 and ‐4 was tested by multiple electrode impedance aggregometry in 82 patients on stable doses of clopidogrel or prasugrel, and in 55 healthy controls. ResultsBased on the consensus cut-off value for adenosine diphosphate (ADP) responsiveness, only one out of 19 patients on prasugrel, but 22 out of 63 patients on clopidogrel had high on-treatment residual platelet reactivity in response to exogenous ADP (p=0.01). Among the patients with adequate ADP P2Y12 receptor inhibition (n=59), we still observed 32 patients (54.2%) with normal response to the PAR-1 activator SFLLRN (26 patients on clopidogrel, 81.2%; 6 patients on prasugrel, 18.8%), and 37 patients (63.8%) with a normal response to the PAR-4 activator AYPGKF (29 patients on clopidogrel, 78.4%; 8 patients on prasugrel, 21.6%). The degree of PAR-agonists inducible platelet activation was directly correlated with the activation induced by ADP (r>0.5 and p<0.001 for both agonists). Moreover, SFLLRN and AYPGKF inducible platelet reactivities were strongly correlated (r=0.75, p<0.001). ConclusionPAR responsiveness is preserved in the majority of patients with adequate clopidogrel-mediated inhibition of the platelet P2Y12 receptor, and still in about 20% of those with adequate inhibition by prasugrel.

Prasugrel Monitoring and Bleeding in Real World Patients

The aim of this study was to evaluate platelet reactivity and 30-day bleeding events in patients treated with prasugrel 10 mg after acute coronary syndromes. A total of 444 patients with acute coronary syndromes treated with percutaneous coronary intervention and prasugrel 10 mg/day were monitored by measurement of the vasodilator-stimulated phosphoprotein (VASP) index 2 to 4 weeks after hospital discharge. Platelet reactivity was also assessed using the VerifyNow P2Y(12) assay and light transmission aggregometry. Bleeding events (per the Bleeding Academic Research Consortium [BARC] definition) and ischemic events (death, myocardial infarction, and definite stent thrombosis) were collected over 30 days of follow-up. Two thirds of the patients presented with ST-segment elevation myocardial infarctions, 28.8% had diabetes, and 12.4% were aged >75 years. High on-treatment platelet reactivity according to 3 prespecified definitions (VASP index ≥ 50%, platelet reactivity ≥ 235 P2Y(12) reaction units, and residual platelet reactivity ≥ 46.2%) was found in 6.8%, 3.4%, and 3.2% of patients, respectively. Obesity (body mass index >30 kg/m(2)) and multivessel disease were the only independent factors associated with high on-treatment platelet reactivity (p = 0.006 and p = 0.045, respectively). At 30 days, there was no major bleeding complication (BARC grade 3 or 5), and 1.6% of patients had recurrent ischemic events. Nuisance bleeding (BARC grade 1) and minor bleeding (BARC grade 2) occurred in 14.2% (n = 63) and 2.5% (n = 11) of patients, respectively, but were not predicted by VASP index. In conclusion, patients with acute coronary syndromes receiving maintenance doses of prasugrel have low rates of HPR and ischemic events within the first month. Minor or minimal bleeding is frequent, but not major bleeding. VASP was poorly correlated with the risk for minor or minimal bleeding.