Explore the vast range of titles available.

The relation between platelet reactivity and stent thrombosis, major bleeding, and other adverse events after coronary artery implantation of drug-eluting stents has been incompletely characterised. We aimed to determine the relation between platelet reactivity during dual therapy with aspirin and clopidogrel and clinical outcomes after successful coronary drug-eluting stent implantation. ADAPT-DES was a prospective, multicentre registry of patients successfully treated with one or more drug-eluting stents and given aspirin and clopidogrel at 10–15 US and European hospitals. We assessed platelet reactivity in those patients after successful percutaneous coronary intervention using VerifyNow point-of-care assays, and assigned different cutoffs to define high platelet reactivity. The primary endpoint was definite or probable stent thrombosis; other endpoints were all-cause mortality, myocardial infarction, and clinically relevant bleeding. We did a propensity-adjusted multivariable analysis to determine the relation between platelet reactivity and subsequent adverse events. This study is registered with ClinicalTrials.gov, number NCT00638794. Between Jan 7, 2008, and Sept 16, 2010, 8665 patients were prospectively enrolled at 11 sites, of which 8583 were eligible. At 1-year follow-up, stent thrombosis had occurred in 70 (0·8%) patients, myocardial infarction in 269 (3·1%), clinically relevant bleeding in 531 (6·2%), and death in 161 (1·9%) patients. High platelet reactivity on clopidogrel was strongly related to stent thrombosis (adjusted HR 2·49 [95% CI 1·43–4·31], p=0·001) and myocardial infarction (adjusted HR 1·42 [1·09–1·86], p=0·01), was inversely related to bleeding (adjusted HR 0·73 [0·61–0·89], p=0·002), but was not related to mortality (adjusted HR 1·20 [0·85–1·70], p=0·30). High platelet reactivity on aspirin was not significantly associated with stent thrombosis (adjusted HR 1·46 [0·58–3·64], p=0·42), myocardial infarction, or death, but was inversely related to bleeding (adjusted HR 0·65 [0·43–0·99], p=0·04). The findings from this study emphasise the counter-balancing effects of haemorrhagic and ischaemic complications after stent implantation, and suggest that safer drugs or tailored strategies for the use of more potent agents must be developed if the benefits of greater platelet inhibition in patients with cardiovascular disease are to be realised. Boston Scientific, Abbott Vascular, Medtronic, Cordis, Biosensors, The Medicines Company, Daiichi-Sankyo, Eli Lilly, Volcano, and Accumetrics

Proton-pump inhibitors (PPIs) are often prescribed in combination with thienopyridines. Conflicting data exist as to whether PPIs diminish the efficacy of clopidogrel. We assessed the association between PPI use, measures of platelet function, and clinical outcomes for patients treated with clopidogrel or prasugrel. In the PRINCIPLE-TIMI 44 trial, the primary outcome was inhibition of platelet aggregation at 6 h assessed by light-transmission aggregometry. In the TRITON-TIMI 38 trial, the primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke. In both studies, PPI use was at physician's discretion. We used a multivariable Cox model with propensity score to assess the association of PPI use with clinical outcomes. In the PRINCIPLE-TIMI 44 trial, 201 patients undergoing elective percutaneous coronary intervention were randomly assigned to prasugrel (n=102) or high-dose clopidogrel (n=99). Mean inhibition of platelet aggregation was significantly lower for patients on a PPI than for those not on a PPI at 6 h after a 600 mg clopidogrel loading dose (23·2±19·5%vs 35·2±20·9%, p=0·02), whereas a more modest difference was seen with and without a PPI after a 60 mg loading dose of prasugrel (69·6±13·5%vs 76·7±12·4%, p=0·054). In the TRITON-TIMI 38 trial, 13 608 patients with an acute coronary syndrome were randomly assigned to prasugrel (n=6813) or clopidogrel (n=6795). In this study, 33% (n=4529) of patients were on a PPI at randomisation. No association existed between PPI use and risk of the primary endpoint for patients treated with clopidogrel (adjusted hazard ratio [HR] 0·94, 95% CI 0·80–1·11) or prasugrel (1·00, 0·84–1·20). The current findings do not support the need to avoid concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel or prasugrel. Daiichi Sankyo Company Limited and Eli Lilly and Company sponsored the trials. This analysis had no funding.

Prospective assessment of pharmacogenetic strategies has been limited by an inability to undertake bedside genetic testing. The CYP2C19*2 allele is a common genetic variant associated with increased rates of major adverse events in individuals given clopidogrel after percutaneous coronary intervention (PCI). We used a novel point-of-care genetic test to identify carriers of the CYP2C19*2 allele and aimed to assess a pharmacogenetic approach to dual antiplatelet treatment after PCI. Between Aug 26, 2010, and July 7, 2011, 200 patients were enrolled into our prospective, randomised, proof-of-concept study. Patients undergoing PCI for acute coronary syndrome or stable angina were randomly assigned to rapid point-of-care genotyping or to standard treatment. Individuals in the rapid genotyping group were screened for the CYP2C19*2 allele. Carriers were given 10 mg prasugrel daily, and non-carriers and patients in the standard treatment group were given 75 mg clopidogrel daily. The primary endpoint was the proportion of CYP2C19*2 carriers with high on-treatment platelet reactivity (P2Y12 reactivity unit [PRU] value of more than 234) after 1 week of dual antiplatelet treatment, which is a marker associated with increased adverse cardiovascular events. Interventional cardiologists and data analysts were masked to genetic status and treatment. Patients were not masked to treatment allocation. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, NCT01184300. After randomisation, 187 patients completed follow-up (91 rapid genotyping group, 96 standard treatment). 23 individuals in each group carried at least one CYP2C19*2 allele. None of the 23 carriers in the rapid genotyping group had a PRU value of more than 234 at day 7, compared with seven (30%) given standard treatment (p=0·0092). The point-of-care genetic test had a sensitivity of 100% (95% CI 92·3–100) and a specificity of 99·3% (96·3–100). Point-of-care genetic testing after PCI can be done effectively at the bedside and treatment of identified CYP2C19*2 carriers with prasugrel can reduce high on-treatment platelet reactivity. Spartan Biosciences.

Ticagrelor (AZD6140) is the first reversibly binding oral P2Y(12) receptor antagonist in development for reduction of clinical thrombotic events in patients with acute coronary syndromes. The purpose of our studies was to determine the effect of single-ascending doses of ticagrelor in healthy subjects. In two randomised, double-blind, placebo-controlled single ascending dose studies, healthy subjects received oral doses of 0.1-100 mg or placebo (n = 25) and 30-400 mg or placebo (n = 13). Absorption of ticagrelor was rapid [median time to peak plasma concentration (t(max)) 1.3-2 h], as was the formation of its main (active) metabolite, AR-C124910XX (t(max) 1.5-3 h). For both ticagrelor and AR-C124910XX, the peak plasma concentration (C(max)) and area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) increased in an apparently dose-proportional manner over the dose range studied, indicating linear pharmacokinetics. The mean terminal-phase half-life (t(1/2)) was approximately 7-8.5 h for ticagrelor and 8.5-10 h for AR-C124910XX; AR-C124910XX exposure was approximately one third that of ticagrelor. Inhibition of platelet aggregation (IPA) was dose related and was nearly complete at 2 h (mean 88-95%; final extent, with 20 microM adenosine diphosphate ADP) at doses of 100-400 mg. Linear and predictable pharmacokinetics of ticagrelor and AR-C124910XX were observed. A consistent and high IPA was maintained over 2-12 h, gradually decreasing with declining plasma concentration starting around 12 h post-dose, indicating that the IPA is reversible. Ticagrelor was well tolerated, with no serious or dose-related adverse events or notable changes in laboratory values observed.

Background Morphine decreases the concentrations and effects of clopidogrel, which could lead to treatment failure in myocardial infarction. Objectives To clarify whether more potent P2Y 12 -inhibitors may provide an effective alternative, we examined drug–drug interactions between morphine and prasugrel. Methods Twelve healthy volunteers received 60 mg prasugrel with placebo or 5 mg morphine intravenously in a randomized, double-blind, placebo-controlled, cross-over trial. Pharmacokinetics were determined by liquid chromatography tandem mass spectrometry, and prasugrel effects were measured by platelet function tests. Results Morphine neither diminished total drug exposure (AUC), which was the primary endpoint, nor significantly delayed drug absorption of prasugrel. However, morphine reduced maximal plasma concentrations ( C max ) of prasugrel active metabolite by 31 % ( p  = 0.019). Morphine slightly, but not significantly, delayed the onset of maximal inhibition of platelet plug formation under high shear rates (30 vs. 20 min). Whole blood aggregation was not influenced. Conclusions Although morphine significantly decreases the maximal plasma concentrations of prasugrel active metabolite, it does not diminish its effects on platelets to a clinically relevant degree in healthy volunteers. However, it should be considered that the observed decrease in C max of prasugrel active metabolite caused by morphine co-administration may gain relevance in STEMI patients. Clinical Trial Registration : NCT01369186, EUDRA-CT#: 2010-023761-22.

The P2Y12 receptor inhibitor prasugrel was approved for thrombotic stroke in Japan following the phase 3 clinical trials PRASTRO-I, -II, and -III. However, correlations between elevated platelet reaction unit (PRU) and ischemic event risk remain unclear. This post hoc integrated analysis of PRASTRO-I, -II, and -III assessed the relationships of PRU with efficacy and safety outcomes, and risk factors for high PRU (HPR). Patients from PRASTRO-I, -II, and -III receiving prasugrel or clopidogrel and with PRU values at 4 and 24 weeks after treatment initiation were included. The primary endpoint was PRU at 4 weeks; secondary endpoints included cumulative incidence of ischemic and bleeding events from study drug initiation to 48 weeks. Exploratory univariate and multivariate analyses were conducted to identify HPR risk factors. Of 2688 patients analyzed, 2595 and 2434 had PRU values available at 4 and 24 weeks, respectively. Mean PRU was numerically lower with prasugrel than clopidogrel at 4 weeks (151.3 vs. 195.4) and 24 weeks (143.8 vs. 188.0). CYP2C19 polymorphisms affected PRU at 4 and 24 weeks with clopidogrel but not with prasugrel. PRU at 4 weeks did not predict ischemic and bleeding event incidence up to 48 weeks. The CYP2C19 poor metabolizer phenotype was the strongest HPR risk factor. PRU values at 4 and 24 weeks were numerically lower with prasugrel and unaffected by CYP2C19 genetic polymorphisms. Further research is needed to clarify the relationship of PRU with ischemic and bleeding events.

Background Despite increased atherothrombotic risk in type 2 diabetes mellitus, (T2DM) the best preventative antithrombotic strategy remains undetermined. We defined the effects of three antiplatelet agents on functional readout and biomarker kinetics in platelet activation and coagulation in patients with T2DM. Materials and methods 56 patients with T2DM were randomised to antiplatelet monotherapy with aspirin 75 mg once daily (OD), clopidogrel 75 mg OD or prasugrel 10 mg OD during three periods of a crossover study. Platelet aggregation (PA) was determined by light-transmittance aggregometry and P-selectin expression by flow cytometry. Markers of fibrin clot dynamics, inflammation and coagulation were measured. Plasma levels of 14 miRNA were assessed by quantitative polymerase chain reactions. Results Of the 56 patients, 24 (43%) were receiving aspirin for primary prevention of ischaemic events and 32 (57%) for secondary prevention. Prasugrel was the strongest inhibitor of ADP-induced PA (mean ± SD maximum response to 20μmol/L ADP 77.6 ± 8.4% [aspirin] vs. 57.7 ± 17.6% [clopidogrel] vs. 34.1 ± 14.1% [prasugrel], p < 0.001), P-selectin expression (30 μmol/L ADP; 45.1 ± 21.4% vs. 27.1 ± 19.0% vs. 14.1 ± 14.9%, p < 0.001) and collagen-induced PA (2 μg/mL; 62.1 ± 19.4% vs. 72.3 ± 18.2% vs. 60.2 ± 18.5%, p < 0.001). Fibrin clot dynamics and levels of coagulation and inflammatory proteins were similar. Lower levels of miR-24 (p = 0.004), miR-191 (p = 0.019), miR-197 (p = 0.009) and miR-223 (p = 0.014) were demonstrated during prasugrel-therapy vs. aspirin. Circulating miR-197 was lower in those cardiovascular disease during therapy with aspirin (p = 0.039) or prasugrel (p = 0.0083). Conclusions Prasugrel monotherapy in T2DM provided potent platelet inhibition and reduced levels of a number of platelet-associated miRNAs. miR-197 is a potential marker of cardiovascular disease in this population. Clinical outcome studies investigating prasugrel monotherapy are warranted in individuals with T2DM. Trial registration EudraCT, 2009-011907-22. Registered 15 March 2010, https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-011907-22/GB .

Background/Objectives: Increasing numbers of food ingredients are gaining acknowledgement, via regulated health claims, of benefits to human health. One such is a water-soluble tomato extract, Fruitflow (FF), a dietary antiplatelet. We examined relative platelet responses to FF and to 75 mg aspirin (ASA) in healthy subjects. Subjects/Methods: A total of 47 healthy subjects completed a double-blinded randomised controlled trial following a crossover design. Acute and 7-day treatments with 75 mg ASA were compared with control with and without concomitant FF, over a 5-h timecourse. Platelet aggregation response agonist, platelet thromboxane A2 release, plasma clotting times and time to form a primary haemostatic clot (PFA-100 closure time, TTC) were measured. Results: Administration of all treatments lowered platelet function and thromboxane A2 generation, and extended the TTC, relative to baseline ( P <0.001) and to control ( P <0.001). Plasma clotting times were not affected. A single 75 mg dose of ASA showed approximately equal efficacy to a dose of FF, whereas daily 75 mg ASA was approximately three times as effective after 7 days ( P =0.002). Platelet responses were heterogenous with distinct weak and strong responder groups. Weak ASA responders retained a functional platelet response to collagen agonist and were responsive to FF. Concomitant FF and ASA did not lead to significant additive effects. Conclusions: The suppression of platelet function observed after consuming FF is approximately one-third that of daily 75 mg ASA. The reversible action of FF renders it less likely to overextend the time to form a primary haemostatic clot than ASA, an important safety consideration for primary prevention.

Objective To determine the individual variability in the response to aspirin and/or clopidogrel and its impact on graft patency after off-pump coronary artery bypass grafting. Design A single-centre prospective randomised controlled study designed according to the Consolidated Standards of Reporting Trials statement. Randomisation was obtained by a computer-generated algorithm. Setting University medical school in Italy. Patients 300 patients who underwent off-pump coronary artery bypass grafting were randomised to receive aspirin (n=150) or aspirin plus clopidogrel (n=150). Intervention Aspirin 100 mg or aspirin 100 mg plus clopidogrel 75 mg daily was initiated when postoperative chest tube drainage was ≤50 ml/h for 2 h and patients were followed up for 12 months. Main outcome measures Qualitative and quantitative assessment of platelet function, angiographic evaluation of coronary revascularisation by 64-slice CT and clinical outcome. Results In the aspirin group, 49 patients (32.6%) were aspirin resistant and, in the aspirin-clopidogrel group, 19 patients (12.6%) were aspirin and clopidogrel resistant. The platelet response to aspirin was similar in all aspirin responders despite the study arm (Aspirin Reaction Units 313.2±44.8 vs 323.6±53.6; p=0.07). The platelet response to clopidogrel was enhanced by aspirin in patients responsive to both aspirin and clopidogrel (synergistic effect) compared with responders to clopidogrel only (P2Y12 Reaction Units 139.9±15.5 vs 179.4±18.5; p<0.001). Combined therapy was associated with a reduced vein graft occlusion rate (7.4% vs 13.1%; p=0.04). Antiplatelet resistance was a predictor of graft occlusion (RR 3.6, 95% CI 2.5 to 6.9; p<0.001). Synergistic aspirin and clopidogrel activity was a strong predictor of vein graft patency (RR 5.1, 95% CI 1.4 to 16.3; p<0.01). Conclusions Combined clopidogrel and aspirin overcome single drug resistances, are safe for bleeding and improve venous graft patency.

Abstract Aims Although dual antiplatelet therapy with aspirin and a potent P2Y12 receptor inhibitor is currently recommended in patients with acute coronary syndrome (ACS), its use in elderly patients remains challenging. The aim of this trial is to evaluate the pharmacodynamic and pharmacokinetic profile of ticagrelor 60 vs. 90 mg twice daily among elderly patients (≥75 years) with ACS undergoing percutaneous coronary intervention (PCI). Methods and results PLINY The ELDER (NCT04739384) was a randomized, crossover trial testing the non-inferiority of a lower vs. standard dose of ticagrelor with respect to the primary endpoint of P2Y12 inhibition as determined by pre-dose P2Y12 reaction units (PRU) using the VerifyNow-P2Y12 (Accumetrics, San Diego, CA, USA). Other pharmacodynamic tests included light transmittance aggregometry, multiple electrode aggregometry, and response to aspirin. Plasma levels of ticagrelor and its active metabolite AR-C124910XX were also evaluated. A total of 50 patients (mean age 79.6 ± 4.0 years, females 44%) were included in the trial. Ticagrelor 60 mg was non-inferior to ticagrelor 90 mg according to VerifyNow-P2Y12 results (PRU 26.4 ± 32.1 vs. 30.4 ± 39.0; least squares mean difference: −4; 95% confidence interval: −16.27 to 8.06; P for non-inferiority = 0.002). Other pharmacodynamic parameters were similar between the two ticagrelor doses and there were no differences in response to aspirin. Plasma levels of ticagrelor (398.29 ± 312.36 ng/mL vs. 579.57 ± 351.73 ng/mL, P = 0.006) and its active metabolite were significantly lower during treatment with ticagrelor 60 mg. Conclusion Although plasma concentrations were lower, ticagrelor 60 mg twice daily provided a similar magnitude of platelet inhibition compared with ticagrelor 90 mg twice daily among elderly patients undergoing PCI. Graphical Abstract Graphical Abstract Inhibition of platelet reactivity following ticagrelor 60 mg vs. 90 mg in elderly patients (≥75 years) undergoing PCI for ACS. A total of 50 older patients with ACS undergoing PCI were randomized to ticagrelor 60 mg vs. 90 mg twice daily. Platelet reactivity was similar and non-inferior between the two ticagrelor maintenance doses, although plasma drug concentrations were significantly lower during treatment with ticagrelor 60 mg. ACS, acute coronary syndrome; LTA, light transmittance aggregometry; MEA, multiple electrode aggregometry; PCI, percutaneous coronary intervention; PRU, P2Y12 reaction units.