Prasugrel

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Eugene Braunwald - One of the best experts on this subject based on the ideXlab platform.

  • discharge aspirin dose and clinical outcomes in patients with acute coronary syndromes treated with Prasugrel versus clopidogrel an analysis from the triton timi 38 study trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with Prasugrel thrombolysis in myocardial infarction 38
    2014
    Co-Authors: Payal Kohli, Elliott M Antman, Eugene Braunwald, Sabina A Murphy, Jacob A Udell, Christopher P Cannon, Stephen D Wiviott
    Abstract:

    Objectives The goal of this study was to determine whether there is a relationship between aspirin dose and the potent antiplatelet agent Prasugrel in the TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction 38) study. Background Optimal aspirin dosing after acute coronary syndromes remains uncertain. Previous studies have raised questions regarding an interaction between high-dose aspirin and the potent antiplatelet agent ticagrelor. Methods In TRITON–TIMI 38, we classified 12,674 patients into low-dose ( Results There was significant geographical variation in aspirin dosing, with North American patients receiving high-dose aspirin more frequently than other countries (66% vs. 28%; p  Conclusions In TRITON–TIMI 38, the safety and efficacy outcomes of Prasugrel compared with those of clopidogrel were directionally consistent regardless of aspirin dose, although only the primary efficacy endpoint achieved statistical significance. There was no clinically meaningful interaction of aspirin with Prasugrel, suggesting that previous observations with potent antiplatelet agents indicating differential results are not universal. (A Comparison of Prasugrel [CS-747] and Clopidogrel in Acute Coronary Syndrome Subjects Who Are to Undergo Percutaneous Coronary Intervention; NCT00097591)

  • efficacy and safety of intensive antiplatelet therapy with Prasugrel from triton timi 38 in a core clinical cohort defined by worldwide regulatory agencies
    2011
    Co-Authors: Stephen D Wiviott, Elliott M Antman, Sabina A Murphy, Nihar R Desai, Guiseppe Musumeci, Michael Ragosta, Eugene Braunwald
    Abstract:

    TRITON-TIMI 38 showed that in patients with acute coronary syndrome undergoing percutaneous coronary intervention Prasugrel decreased ischemic events compared to standard clopidogrel, but with more bleeding. The United States Food and Drug Administration and the European Medicines Agency approved Prasugrel but provided contraindications in patients with previous stroke or transient ischemic attack and recommended limited use or reduced dose in patients ≥75 years old and weighing 60 kg had substantial decreases in ischemic events with Prasugrel compared to clopidogrel. Although relative bleeding excess exists in this population, absolute rates and differences in bleeding were attenuated. In conclusion, these data indicate that use of Prasugrel in a core clinical cohort that has been defined by regulatory action will maximize the benefit of Prasugrel and limit the risk of adverse outcomes.

  • cost effectiveness of Prasugrel versus clopidogrel in patients with acute coronary syndromes and planned percutaneous coronary intervention results from the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with pr
    2010
    Co-Authors: Elizabeth M Mahoney, Kaijun Wang, Suzanne V Arnold, Irina Proskorovsky, Stephen D Wiviott, Elliott M Antman, Eugene Braunwald, David J Cohen
    Abstract:

    Background— In patients with acute coronary syndromes and planned percutaneous coronary intervention, the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) demonstrated that treatment with Prasugrel versus clopidogrel was associated with reduced rates of cardiovascular death, MI, or stroke and an increased risk of major bleeding. We evaluated the cost-effectiveness of Prasugrel versus clopidogrel from the perspective of the US healthcare system by using data from TRITON-TIMI 38. Methods and Results— Detailed resource use data were prospectively collected for all patients recruited from 8 countries (United States, Australia, Canada, Germany, Italy, Spain, United Kingdom, and France; n=3373 Prasugrel, n=3332 clopidogrel). Hospitalization costs were estimated on the basis of diagnosis-related group and in-hospital complications. Cardiovascular medication costs were estimated by using net wholesale pri...

  • effect of Prasugrel versus clopidogrel on outcomes among patients with acute coronary syndrome undergoing percutaneous coronary intervention without stent implantation a trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with Prasugrel triton thrombolysis in myocardial infarction timi 38 substudy
    2009
    Co-Authors: Yuri B Pride, Stephen D Wiviott, Elliott M Antman, Eugene Braunwald, Jacqueline L Buros, Cafer Zorkun, Umer M Tariq, Michael C Gibson
    Abstract:

    Background Prasugrel led to a significant reduction in ischemic cardiovascular events among patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) with stent implantation compared to clopidogrel. Whether this benefit extends to patients undergoing PCI without stent implantation is unknown. Methods In TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with Prasugrel (TRITON)-Thrombolysis in Myocardial Infarction (TIMI) 38, patients (n = 13 608) undergoing PCI for ACS were randomized to aspirin plus clopidogrel or Prasugrel. This postrandomization analysis of a prespecified subgroup was restricted to patients who underwent PCI without stent implantation (n = 569). Results Patients who underwent PCI without stent implantation were older and had a higher incidence of hypertension, diabetes, prior myocardial infarction (MI), prior coronary artery bypass (CABG) surgery, and renal dysfunction than patients who underwent stent implantation. In the group that did not undergo stent implantation, baseline characteristics were similar between patients receiving clopidogrel and Prasugrel. The composite of cardiovascular death, nonfatal MI, and nonfatal stroke occurred in 14.2% of patients receiving Prasugrel and 17.1% of patients receiving clopidogrel (HR 0.82, P = .27). There were significant reductions favoring Prasugrel in the rates of urgent target vessel revascularization (TVR; HR 0.46, P = .040) and any TVR (HR 0.40, P = .009) and a trend toward a reduction in the incidence of nonfatal MI (HR 0.65, P = .11). CABG-related TIMI major bleeding was more frequent among patients receiving Prasugrel. There were no significant interactions between treatment and PCI type. Conclusion Among ACS patients who underwent PCI without stent implantation, Prasugrel therapy tended to reduce clinical ischemic events and to increase bleeding events to a similar magnitude as among patients who received stents.

  • the efficacy and safety of Prasugrel with and without a glycoprotein iib iiia inhibitor in patients with acute coronary syndromes undergoing percutaneous intervention a triton timi 38 trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with Prasugrel thrombolysis in myocardial infarction 38 analysis
    2009
    Co-Authors: Michelle L Odonoghue, Elliott M Antman, Eugene Braunwald, Carolyn H Mccabe, Sabina A Murphy, Gabriel P Steg, Ariel Finkelstein, William F Penny, Viliam Fridrich, Marc S Sabatine
    Abstract:

    Objectives We evaluated the efficacy and safety of Prasugrel and clopidogrel in the setting of a glycoprotein (GP) IIb/IIIa inhibitor. Background Prasugrel reduced cardiovascular events as compared with clopidogrel in TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38) but with increased bleeding. Methods Researchers in the TRITON–TIMI 38 randomized 13,608 subjects with acute coronary syndrome undergoing percutaneous coronary intervention to Prasugrel versus clopidogrel. The use of a GP IIb/IIIa inhibitor was at the physician's discretion. For the current analysis, end points were examined at 30 days and were stratified by use of a GP IIb/IIIa inhibitor. Results A total of 7,414 subjects (54.5%) received a GP IIb/IIIa inhibitor during their index hospitalization. There was a consistent benefit of Prasugrel over clopidogrel for reducing cardiovascular death, myocardial infarction, or stroke in patients who did (hazard ratio: 0.76; 95% confidence interval: 0.64 to 0.90) or did not receive a GP IIb/IIIa inhibitor (hazard ratio: 0.78; 95% confidence interval: 0.63 to 0.97, p interaction = 0.83). Prasugrel significantly reduced myocardial infarction, urgent revascularization, and stent thrombosis irrespective of GP IIb/IIIa inhibitor use. Although subjects treated with a GP IIb/IIIa inhibitor had greater rates of bleeding, the risk of Thrombolysis in Myocardial Infarction major or minor bleeding with Prasugrel versus clopidogrel was not significantly different in patients who were or were not treated with GP IIb/IIIa inhibitor (p interaction = 0.19). Conclusions Prasugrel significantly reduces the risk of cardiovascular events in patients with acute coronary syndromes after percutaneous coronary intervention regardless of whether or not a GP IIb/IIIa inhibitor is used. The use of a GP IIb/IIIa inhibitor does not accentuate the relative risk of bleeding with Prasugrel as compared with clopidogrel.

Joseph A. Jakubowski - One of the best experts on this subject based on the ideXlab platform.

  • Cangrelor inhibits the binding of the active metabolites of clopidogrel and Prasugrel to P2Y12 receptors in vitro
    2015
    Co-Authors: Heather M. Judge, Joseph A. Jakubowski, Robert J. Buckland, Robert F. Storey
    Abstract:

    Cangrelor is a rapid-acting, direct-binding, and reversible P2Y12 antagonist which has been studied for use during percutaneous coronary intervention (PCI) in patients with or without pretreatment with an oral P2Y12 antagonist. As cangrelor is administered intravenously, it is necessary to switch to an oral P2Y12 antagonist following PCI, such as the thienopyridines clopidogrel, and Prasugrel or the non-pyridine ticagrelor. Previous studies have suggested a negative pharmacodynamic interaction between cangrelor and thienopyridines. This in vitro study evaluated the receptor-level interaction between cangrelor and the active metabolite (AM) of clopidogrel or Prasugrel by assessing functional P2Y12 receptor number using a (33)P-2MeSADP binding assay. All P2Y12 antagonists studied resulted in strong P2Y12 receptor blockade (cangrelor: 93.6%; clopidogrel AM: 93.0%; Prasugrel AM: 97.9%). Adding a thienopyridine AM in the presence of cangrelor strongly reduces P2Y12 receptor blockade by the AM (clopidogrel AM: 7%, Prasugrel AM: 3.2%). The thienopyridine AMs had limited ability to compete with cangrelor for binding to P2Y12 (% P2Y12 receptor blockade after co-incubation with cangrelor 1000 nmol/L: 11.7% for clopidogrel AM 3 µmol/L; 34.1% for Prasugrel AM 3 µmol/L). In conclusion, in vitro cangrelor strongly inhibits the binding of clopidogrel and Prasugrel AMs to the P2Y12 receptor, consistent with the previous observation of a negative pharmacodynamic interaction. Care may need to be taken to not overlap exposure to thienopyridine AMs and cangrelor in order to reduce the risk of thrombotic complications following PCI.

  • pharmacodynamic evaluation of switching from ticagrelor to Prasugrel in patients with stable coronary artery disease results of the swap 2 study switching anti platelet 2
    2014
    Co-Authors: Dominick J Angiolillo, Joseph A. Jakubowski, Mark B Effron, Paul A Gurbel, Nick Curzen, Paul T Vaitkus, Fred Lipkin, Marjorie Zettler, Dietmar Trenk
    Abstract:

    Objectives The goal of this study was to evaluate the pharmacodynamic effects of switching patients from ticagrelor to Prasugrel. Background Clinicians may need to switch between more potent P2Y12 inhibitors because of adverse effects or switch to the use of a once-daily dosing regimen due to compliance issues. Methods After a 3- to 5-day run-in phase with a ticagrelor 180-mg loading dose (LD) followed by a ticagrelor 90-mg twice-daily maintenance dose (MD), aspirin-treated patients (N = 110) with stable coronary artery disease were randomized to continue ticagrelor or switch to Prasugrel 10-mg once-daily MD, with or without a 60-mg LD. Pharmacodynamic assessments were defined according to P2Y12 reaction unit (PRU) (P2Y12 assay) and platelet reactivity index (vasodilator-stimulated phosphoprotein phosphorylation assay) at baseline (before and after the run-in phase) and 2, 4, 24, and 48 h and 7 days after randomization. Results Platelet reactivity was significantly greater at 24 and 48 h after switching to Prasugrel versus continued therapy with ticagrelor, although to a lesser extent in those receiving an LD. Mean PRU remained significantly higher in the combined Prasugrel groups versus the ticagrelor group (least-squares mean difference: 46 [95% confidence interval 25 to 67]) and did not meet the primary noninferiority endpoint (upper limit of the confidence interval ≤45), although PRU in the Prasugrel cohort was lower at 7 days than at 24 or 48 h. Accordingly, rates of high on-treatment platelet reactivity were higher at 24 and 48 h in both Prasugrel groups. At 7 days, there was no difference in high on-treatment platelet reactivity rate between the combined Prasugrel and ticagrelor groups. Conclusions Compared with continued ticagrelor therapy, switching from ticagrelor to Prasugrel therapy was associated with an increase in platelet reactivity that was partially mitigated by the administration of an LD.

  • enhanced active metabolite generation and platelet inhibition with Prasugrel compared to clopidogrel regardless of genotype in thienopyridine metabolic pathways
    2013
    Co-Authors: Oscar O Braun, Kenneth J Winters, Joseph A. Jakubowski, José Luis Ferreiro, Dominick J Angiolillo, Mark B Effron, Timothy M Costigan, Suman Duvvuru, Scott S Sundseth, Joseph R Walker
    Abstract:

    Clopidogrel response varies according to the presence of genetic polymorphisms. The CYP2C19*2 allele has been associated with impaired response; conflicting results have been reported for CYP2C19*17, ABCB1, and PON1 genotypes. We assessed the impact of CYP2C19, PON1, and ABCB1 polymorphisms on clopidogrel and Prasugrel pharmacodynamic (PD) and pharmacokinetic (PK) parameters. Aspirin-treated patients (N=194) with coronary artery disease from two independent, prospective, randomised, multi-centre studies comparing clopidogrel (75 mg) and Prasugrel (10 mg) were genotyped and classified by predicted CYP2C19 metaboliser phenotype (ultra metabolisers [UM] = *17 carriers; extensive metabolisers [EM] = *1/1 homozygotes; reduced metabolisers [RM] = *2 carriers). ABCB1 T/T and C/T polymorphisms and PON1 A/A, A/G and G/G polymorphisms were also genotyped. PD parameters were assessed using VerifyNow® P2Y12 and vasodilator stimulated phosphoprotein (VASP) expressed as platelet reactivity index (PRI) after 14 days of maintenance dosing. Clopidogrel and Prasugrel active metabolite (AM) exposure was calculated in a cohort of 96 patients. For clopidogrel, genetic variants in CYP2C19, but not ABCB1 or PON1, affected PK and PD. For Prasugrel, none of the measured genetic variants affected PK or PD. Compared with clopidogrel, platelet inhibition with Prasugrel was greater even in the CYP2C19 UM phenotype. Prasugrel generated more AM and achieved greater platelet inhibition than clopidogrel irrespective of CYP2C19, ABCB1, and PON1 polymorphisms. The lack of effect from genetic variants on Prasugrel AM generation or antiplatelet activity is consistent with previous studies in healthy volunteers and is consistent with improved efficacy in acute coronary syndrome patients managed with percutaneous coronary intervention.

  • the influence of smoking status on the pharmacokinetics and pharmacodynamics of clopidogrel and Prasugrel the paradox study
    2013
    Co-Authors: Paul A Gurbel, Dominick J Angiolillo, Douglas Logan, Kevin P Bliden, Dean J Kereiakes, Kenneth C Lasseter, Alex White, Thomas D Nolin, William L Bailey, Joseph A. Jakubowski
    Abstract:

    Objectives The goal of this study was to evaluate the effect of smoking on the pharmacokinetics and pharmacodynamics (PD) of clopidogrel and Prasugrel therapy. Background Major randomized trial data demonstrated that nonsmokers experience less or no benefit from clopidogrel treatment compared with smokers (i.e., the “smokers9 paradox”). Methods PARADOX was a prospective, randomized, double-blind, double-dummy, placebo-controlled, crossover study of objectively assessed nonsmokers (n = 56) and smokers (n = 54) with stable coronary artery disease receiving aspirin therapy. Patients were randomized to receive clopidogrel (75 mg daily) or Prasugrel (10 mg daily) for 10 days and crossed over after a 14-day washout. PD was assessed by using VerifyNow P2Y12 and vasodilator-stimulated phosphoprotein phosphorylation assays. Clopidogrel and Prasugrel metabolite levels, cytochrome P450 1A2 activity, CYP2C19 genotype, and safety parameters were determined. Results During clopidogrel therapy, device-reported inhibition of platelet aggregation (IPA) trended lower in nonsmokers than smokers (least squares mean treatment difference ± SE: 7.7 ± 4.1%; p = 0.062). Device-reported IPA was significantly lower in clopidogrel-treated smokers than Prasugrel-treated smokers (least squares mean treatment difference: 31.8 ± 3.4%; p  Conclusions PARADOX demonstrated lower clopidogrel active metabolite exposure and PD effects of clopidogrel in nonsmokers relative to smokers. Prasugrel was associated with greater active metabolite exposure and PD effects than clopidogrel regardless of smoking status. The poorer antiplatelet response in clopidogrel-treated nonsmokers may provide an explanation for the smokers9 paradox. (The Influence of Smoking Status on Prasugrel and Clopidogrel Treated Subjects Taking Aspirin and Having Stable Coronary Artery Disease; NCT01260584)

  • decrease in high on treatment platelet reactivity hpr prevalence on switching from clopidogrel to Prasugrel insights from the switching anti platelet swap study
    2012
    Co-Authors: Jorge F Saucedo, Joseph A. Jakubowski, Dominick J Angiolillo, Roger Deraad, Andrew L Frelinger, Paul A Gurbel, Timothy M Costigan, Clement K Ojeh, Suman Duvvuru, Mark B Effron
    Abstract:

    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%, p235 (18.8% vs. 0%, p=0.001), and PRI ≥ 50 % (66.7% vs. 7.9%, p65% (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.

Stephen D Wiviott - One of the best experts on this subject based on the ideXlab platform.

  • early clopidogrel versus Prasugrel use among contemporary stemi and nstemi patients in the us insights from the national cardiovascular data registry
    2014
    Co-Authors: Matthew W Sherwood, Stephen D Wiviott, Andrew S Peng, Matthew T Roe, James Delemos, Eric D Peterson, Tracy Y Wang
    Abstract:

    Background P2Y12 antagonist therapy improves outcomes in acute myocardial infarction (MI) patients. Novel agents in this class are now available in the US. We studied the introduction of Prasugrel into contemporary MI practice to understand the appropriateness of its use and assess for changes in antiplatelet management practices. Methods and Results Using ACTION Registry-GWTG (Get-with-the-Guidelines), we evaluated patterns of P2Y12 antagonist use within 24 hours of admission in 100 228 ST elevation myocardial infarction (STEMI) and 158 492 Non-ST elevation myocardial infarction (NSTEMI) patients at 548 hospitals between October 2009 and September 2012. Rates of early P2Y12 antagonist use were approximately 90% among STEMI and 57% among NSTEMI patients. From 2009 to 2012, Prasugrel use increased significantly from 3% to 18% (5% to 30% in STEMI; 2% to 10% in NSTEMI; P for trend <0.001 for all). During the same period, we observed a decrease in use of early but not discharge P2Y12 antagonist among NSTEMI patients. Although contraindicated, 3.0% of patients with prior stroke received Prasugrel. Prasugrel was used in 1.9% of patients ≥75 years and 4.5% of patients with weight <60 kg. In both STEMI and NSTEMI, Prasugrel was most frequently used in patients at the lowest predicted risk for bleeding and mortality. Despite lack of supporting evidence, Prasugrel was initiated before cardiac catheterization in 18% of NSTEMI patients. Conclusions With Prasugrel as an antiplatelet treatment option, contemporary practice shows low uptake of Prasugrel and delays in P2Y12 antagonist initiation among NSTEMI patients. We also note concerning evidence of inappropriate use of Prasugrel, and inadequate targeting of this more potent therapy to maximize the benefit/risk ratio.

  • discharge aspirin dose and clinical outcomes in patients with acute coronary syndromes treated with Prasugrel versus clopidogrel an analysis from the triton timi 38 study trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with Prasugrel thrombolysis in myocardial infarction 38
    2014
    Co-Authors: Payal Kohli, Elliott M Antman, Eugene Braunwald, Sabina A Murphy, Jacob A Udell, Christopher P Cannon, Stephen D Wiviott
    Abstract:

    Objectives The goal of this study was to determine whether there is a relationship between aspirin dose and the potent antiplatelet agent Prasugrel in the TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction 38) study. Background Optimal aspirin dosing after acute coronary syndromes remains uncertain. Previous studies have raised questions regarding an interaction between high-dose aspirin and the potent antiplatelet agent ticagrelor. Methods In TRITON–TIMI 38, we classified 12,674 patients into low-dose ( Results There was significant geographical variation in aspirin dosing, with North American patients receiving high-dose aspirin more frequently than other countries (66% vs. 28%; p  Conclusions In TRITON–TIMI 38, the safety and efficacy outcomes of Prasugrel compared with those of clopidogrel were directionally consistent regardless of aspirin dose, although only the primary efficacy endpoint achieved statistical significance. There was no clinically meaningful interaction of aspirin with Prasugrel, suggesting that previous observations with potent antiplatelet agents indicating differential results are not universal. (A Comparison of Prasugrel [CS-747] and Clopidogrel in Acute Coronary Syndrome Subjects Who Are to Undergo Percutaneous Coronary Intervention; NCT00097591)

  • efficacy and safety of intensive antiplatelet therapy with Prasugrel from triton timi 38 in a core clinical cohort defined by worldwide regulatory agencies
    2011
    Co-Authors: Stephen D Wiviott, Elliott M Antman, Sabina A Murphy, Nihar R Desai, Guiseppe Musumeci, Michael Ragosta, Eugene Braunwald
    Abstract:

    TRITON-TIMI 38 showed that in patients with acute coronary syndrome undergoing percutaneous coronary intervention Prasugrel decreased ischemic events compared to standard clopidogrel, but with more bleeding. The United States Food and Drug Administration and the European Medicines Agency approved Prasugrel but provided contraindications in patients with previous stroke or transient ischemic attack and recommended limited use or reduced dose in patients ≥75 years old and weighing 60 kg had substantial decreases in ischemic events with Prasugrel compared to clopidogrel. Although relative bleeding excess exists in this population, absolute rates and differences in bleeding were attenuated. In conclusion, these data indicate that use of Prasugrel in a core clinical cohort that has been defined by regulatory action will maximize the benefit of Prasugrel and limit the risk of adverse outcomes.

  • cost effectiveness of Prasugrel versus clopidogrel in patients with acute coronary syndromes and planned percutaneous coronary intervention results from the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with pr
    2010
    Co-Authors: Elizabeth M Mahoney, Kaijun Wang, Suzanne V Arnold, Irina Proskorovsky, Stephen D Wiviott, Elliott M Antman, Eugene Braunwald, David J Cohen
    Abstract:

    Background— In patients with acute coronary syndromes and planned percutaneous coronary intervention, the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) demonstrated that treatment with Prasugrel versus clopidogrel was associated with reduced rates of cardiovascular death, MI, or stroke and an increased risk of major bleeding. We evaluated the cost-effectiveness of Prasugrel versus clopidogrel from the perspective of the US healthcare system by using data from TRITON-TIMI 38. Methods and Results— Detailed resource use data were prospectively collected for all patients recruited from 8 countries (United States, Australia, Canada, Germany, Italy, Spain, United Kingdom, and France; n=3373 Prasugrel, n=3332 clopidogrel). Hospitalization costs were estimated on the basis of diagnosis-related group and in-hospital complications. Cardiovascular medication costs were estimated by using net wholesale pri...

  • effect of Prasugrel versus clopidogrel on outcomes among patients with acute coronary syndrome undergoing percutaneous coronary intervention without stent implantation a trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with Prasugrel triton thrombolysis in myocardial infarction timi 38 substudy
    2009
    Co-Authors: Yuri B Pride, Stephen D Wiviott, Elliott M Antman, Eugene Braunwald, Jacqueline L Buros, Cafer Zorkun, Umer M Tariq, Michael C Gibson
    Abstract:

    Background Prasugrel led to a significant reduction in ischemic cardiovascular events among patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) with stent implantation compared to clopidogrel. Whether this benefit extends to patients undergoing PCI without stent implantation is unknown. Methods In TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with Prasugrel (TRITON)-Thrombolysis in Myocardial Infarction (TIMI) 38, patients (n = 13 608) undergoing PCI for ACS were randomized to aspirin plus clopidogrel or Prasugrel. This postrandomization analysis of a prespecified subgroup was restricted to patients who underwent PCI without stent implantation (n = 569). Results Patients who underwent PCI without stent implantation were older and had a higher incidence of hypertension, diabetes, prior myocardial infarction (MI), prior coronary artery bypass (CABG) surgery, and renal dysfunction than patients who underwent stent implantation. In the group that did not undergo stent implantation, baseline characteristics were similar between patients receiving clopidogrel and Prasugrel. The composite of cardiovascular death, nonfatal MI, and nonfatal stroke occurred in 14.2% of patients receiving Prasugrel and 17.1% of patients receiving clopidogrel (HR 0.82, P = .27). There were significant reductions favoring Prasugrel in the rates of urgent target vessel revascularization (TVR; HR 0.46, P = .040) and any TVR (HR 0.40, P = .009) and a trend toward a reduction in the incidence of nonfatal MI (HR 0.65, P = .11). CABG-related TIMI major bleeding was more frequent among patients receiving Prasugrel. There were no significant interactions between treatment and PCI type. Conclusion Among ACS patients who underwent PCI without stent implantation, Prasugrel therapy tended to reduce clinical ischemic events and to increase bleeding events to a similar magnitude as among patients who received stents.

Dominick J Angiolillo - One of the best experts on this subject based on the ideXlab platform.

  • pharmacodynamic evaluation of switching from ticagrelor to Prasugrel in patients with stable coronary artery disease results of the swap 2 study switching anti platelet 2
    2014
    Co-Authors: Dominick J Angiolillo, Joseph A. Jakubowski, Mark B Effron, Paul A Gurbel, Nick Curzen, Paul T Vaitkus, Fred Lipkin, Marjorie Zettler, Dietmar Trenk
    Abstract:

    Objectives The goal of this study was to evaluate the pharmacodynamic effects of switching patients from ticagrelor to Prasugrel. Background Clinicians may need to switch between more potent P2Y12 inhibitors because of adverse effects or switch to the use of a once-daily dosing regimen due to compliance issues. Methods After a 3- to 5-day run-in phase with a ticagrelor 180-mg loading dose (LD) followed by a ticagrelor 90-mg twice-daily maintenance dose (MD), aspirin-treated patients (N = 110) with stable coronary artery disease were randomized to continue ticagrelor or switch to Prasugrel 10-mg once-daily MD, with or without a 60-mg LD. Pharmacodynamic assessments were defined according to P2Y12 reaction unit (PRU) (P2Y12 assay) and platelet reactivity index (vasodilator-stimulated phosphoprotein phosphorylation assay) at baseline (before and after the run-in phase) and 2, 4, 24, and 48 h and 7 days after randomization. Results Platelet reactivity was significantly greater at 24 and 48 h after switching to Prasugrel versus continued therapy with ticagrelor, although to a lesser extent in those receiving an LD. Mean PRU remained significantly higher in the combined Prasugrel groups versus the ticagrelor group (least-squares mean difference: 46 [95% confidence interval 25 to 67]) and did not meet the primary noninferiority endpoint (upper limit of the confidence interval ≤45), although PRU in the Prasugrel cohort was lower at 7 days than at 24 or 48 h. Accordingly, rates of high on-treatment platelet reactivity were higher at 24 and 48 h in both Prasugrel groups. At 7 days, there was no difference in high on-treatment platelet reactivity rate between the combined Prasugrel and ticagrelor groups. Conclusions Compared with continued ticagrelor therapy, switching from ticagrelor to Prasugrel therapy was associated with an increase in platelet reactivity that was partially mitigated by the administration of an LD.

  • enhanced active metabolite generation and platelet inhibition with Prasugrel compared to clopidogrel regardless of genotype in thienopyridine metabolic pathways
    2013
    Co-Authors: Oscar O Braun, Kenneth J Winters, Joseph A. Jakubowski, José Luis Ferreiro, Dominick J Angiolillo, Mark B Effron, Timothy M Costigan, Suman Duvvuru, Scott S Sundseth, Joseph R Walker
    Abstract:

    Clopidogrel response varies according to the presence of genetic polymorphisms. The CYP2C19*2 allele has been associated with impaired response; conflicting results have been reported for CYP2C19*17, ABCB1, and PON1 genotypes. We assessed the impact of CYP2C19, PON1, and ABCB1 polymorphisms on clopidogrel and Prasugrel pharmacodynamic (PD) and pharmacokinetic (PK) parameters. Aspirin-treated patients (N=194) with coronary artery disease from two independent, prospective, randomised, multi-centre studies comparing clopidogrel (75 mg) and Prasugrel (10 mg) were genotyped and classified by predicted CYP2C19 metaboliser phenotype (ultra metabolisers [UM] = *17 carriers; extensive metabolisers [EM] = *1/1 homozygotes; reduced metabolisers [RM] = *2 carriers). ABCB1 T/T and C/T polymorphisms and PON1 A/A, A/G and G/G polymorphisms were also genotyped. PD parameters were assessed using VerifyNow® P2Y12 and vasodilator stimulated phosphoprotein (VASP) expressed as platelet reactivity index (PRI) after 14 days of maintenance dosing. Clopidogrel and Prasugrel active metabolite (AM) exposure was calculated in a cohort of 96 patients. For clopidogrel, genetic variants in CYP2C19, but not ABCB1 or PON1, affected PK and PD. For Prasugrel, none of the measured genetic variants affected PK or PD. Compared with clopidogrel, platelet inhibition with Prasugrel was greater even in the CYP2C19 UM phenotype. Prasugrel generated more AM and achieved greater platelet inhibition than clopidogrel irrespective of CYP2C19, ABCB1, and PON1 polymorphisms. The lack of effect from genetic variants on Prasugrel AM generation or antiplatelet activity is consistent with previous studies in healthy volunteers and is consistent with improved efficacy in acute coronary syndrome patients managed with percutaneous coronary intervention.

  • the influence of smoking status on the pharmacokinetics and pharmacodynamics of clopidogrel and Prasugrel the paradox study
    2013
    Co-Authors: Paul A Gurbel, Dominick J Angiolillo, Douglas Logan, Kevin P Bliden, Dean J Kereiakes, Kenneth C Lasseter, Alex White, Thomas D Nolin, William L Bailey, Joseph A. Jakubowski
    Abstract:

    Objectives The goal of this study was to evaluate the effect of smoking on the pharmacokinetics and pharmacodynamics (PD) of clopidogrel and Prasugrel therapy. Background Major randomized trial data demonstrated that nonsmokers experience less or no benefit from clopidogrel treatment compared with smokers (i.e., the “smokers9 paradox”). Methods PARADOX was a prospective, randomized, double-blind, double-dummy, placebo-controlled, crossover study of objectively assessed nonsmokers (n = 56) and smokers (n = 54) with stable coronary artery disease receiving aspirin therapy. Patients were randomized to receive clopidogrel (75 mg daily) or Prasugrel (10 mg daily) for 10 days and crossed over after a 14-day washout. PD was assessed by using VerifyNow P2Y12 and vasodilator-stimulated phosphoprotein phosphorylation assays. Clopidogrel and Prasugrel metabolite levels, cytochrome P450 1A2 activity, CYP2C19 genotype, and safety parameters were determined. Results During clopidogrel therapy, device-reported inhibition of platelet aggregation (IPA) trended lower in nonsmokers than smokers (least squares mean treatment difference ± SE: 7.7 ± 4.1%; p = 0.062). Device-reported IPA was significantly lower in clopidogrel-treated smokers than Prasugrel-treated smokers (least squares mean treatment difference: 31.8 ± 3.4%; p  Conclusions PARADOX demonstrated lower clopidogrel active metabolite exposure and PD effects of clopidogrel in nonsmokers relative to smokers. Prasugrel was associated with greater active metabolite exposure and PD effects than clopidogrel regardless of smoking status. The poorer antiplatelet response in clopidogrel-treated nonsmokers may provide an explanation for the smokers9 paradox. (The Influence of Smoking Status on Prasugrel and Clopidogrel Treated Subjects Taking Aspirin and Having Stable Coronary Artery Disease; NCT01260584)

  • decrease in high on treatment platelet reactivity hpr prevalence on switching from clopidogrel to Prasugrel insights from the switching anti platelet swap study
    2012
    Co-Authors: Jorge F Saucedo, Joseph A. Jakubowski, Dominick J Angiolillo, Roger Deraad, Andrew L Frelinger, Paul A Gurbel, Timothy M Costigan, Clement K Ojeh, Suman Duvvuru, Mark B Effron
    Abstract:

    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%, p235 (18.8% vs. 0%, p=0.001), and PRI ≥ 50 % (66.7% vs. 7.9%, p65% (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.

  • reduction in platelet reactivity with Prasugrel 5 mg in low body weight patients is noninferior to Prasugrel 10 mg in higher body weight patients results from the feather trial
    2012
    Co-Authors: David Erlinge, Joseph A. Jakubowski, Jurrien Ten M Berg, David P Foley, Dominick J Angiolillo, Henrik Wagner, Patricia B Brown, Chunmei Zhou, Junxiang Luo, Brian A Moser
    Abstract:

    Objectives The aim of this study was to confirm prior modeling data suggesting that Prasugrel 5 mg in low-body-weight (LBW) patients would be noninferior to Prasugrel 10 mg in higher-body-weight (HBW) patients as assessed by maximal platelet aggregation (MPA). Background Prasugrel 10 mg reduced ischemic events compared with clopidogrel 75 mg but increased bleeding, particularly in LBW patients. Methods In this blinded, 3-period, crossover study in stable patients with coronary artery disease (CAD) taking aspirin, Prasugrel 5 and 10 mg and clopidogrel 75 mg were administered to LBW (56.4 ± 3.7 kg; n = 34) and HBW patients (84.7 ± 14.9 kg; n = 38). Assays included light transmission aggregometry (LTA), VerifyNow P2Y12 (VN), and vasodilator-associated stimulated phosphoprotein (VASP) level measured predose and after each 12-day treatment. Results Median MPA by LTA for Prasugrel 5 mg in LBW patients was noninferior to the 75th percentile for Prasugrel 10 mg in HBW patients (primary endpoint) and mean MPA was similar, but active metabolite exposure was lowered by 38%. Within LBW patients, Prasugrel 5 mg lowered MPA more than clopidogrel (least squares mean difference [95% confidence interval]: −3.7% [−6.72%, −0.69%]) and resulted in lower rates of high on-treatment platelet reactivity (HPR). Within HBW patients, Prasugrel 10 mg lowered MPA more than clopidogrel (−16.9% [−22.3%, −11.5%]). Similar results were observed by VN and VASP. Prasugrel 10 mg in LBW patients was associated with more mild to moderate bleeding (mainly bruising) compared with Prasugrel 5 mg and clopidogrel. Conclusions In aspirin-treated patients with CAD, Prasugrel 5 mg in LBW patients reduced platelet reactivity to a similar extent as Prasugrel 10 mg in HBW patients and resulted in greater platelet inhibition, lower HPR, and similar bleeding rates compared with clopidogrel. (Comparison of Prasugrel and Clopidogrel in Low Body Weight Versus Higher Body Weight With Coronary Artery Disease [FEATHER]; NCT01107925 )

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