Abstract 5603: Oral Dosing of PRT060128, a Novel Direct-acting, Reversible P2Y 12 Antagonist Overcomes High Platelet Reactivity in Patients Non-responsive to Clopidogrel Therapy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Paul A Gurbel ◽  
Pamela B Conley ◽  
Patrick Andre ◽  
Gillian Stephens ◽  
Daniel D Gretler ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Platelet Function ◽  
Large Scale ◽  
Platelet Reactivity ◽  
Light Transmittance ◽  
High Platelet Reactivity ◽  
Clopidogrel Therapy ◽  
Direct Acting ◽  
Induced Aggregation

Introduction: The ADP receptor P2Y 12 plays a central role in platelet function. Clopidogrel therapy is associated with various limitations including irreversible inhibition, a delayed antiplatelet effect, wide response variability, and non-responsiveness that has been linked to adverse ischemic event occurrence. We report the first pharmacodynamic study of a single oral dose of PRT060128 (PRT128), a novel, direct-acting reversible P2Y 12 inhibitor in patients with high platelet reactivity while on maintenance dose clopidogrel therapy(75mg/d) and aspirin. Methods: Previously stented patients (n=27) on maintenance aspirin and clopidogrel therapy were screened for high platelet reactivity (HPR) defined as upper tertile 5μ M ADP-induced aggregation (>43%) based on prior studies conducted at our Center; 7/27 had HPR and were treated with a single oral dose (60 mg) of PRT128. Platelet function was assessed at baseline, 4 hours, 6 hours, and 24 hours post-dosing by light transmittance aggregometry (LTA) stimulated by 5μ M, 20 μ M ADP, and 4μ g/ml collagen; Thrombelastography PlateletMapping (MA ADP ), Accumetrics P2Y12 assay (PRU), platelet reactivity ratio (%) by vasodilator stimulated phosphoprotein phosphorylation (VASP), and Perfusion Chamber Assay (PCA). Results: Results shown in the Table represent means ± standard deviation for the 7 patients at each time point. Conclusion: Based on results using multiple pharmacodynamic assays, PRT060128 is a potent rapid-acting inhibitor of P2Y 12 that overcomes high platelet reactivity in patients non-responsive to clopidogrel therapy. The pharmacodynamic properties of this novel P2Y 12 antagonist warrant future large scale investigations to determine clinical efficacy.

Platelet function profiles in the elderly: Results of a pharmacodynamic study in patients on clopidogrel therapy and effects of switching to prasugrel 5 mg in patients with high platelet reactivity

2011 ◽  
Vol 106 (12) ◽  
pp. 1149-1157 ◽  
Author(s):  
Claudia Tamburino ◽  
Davide Capodanno ◽  
Eligio Miccichè ◽  
Lucia D’Urso ◽  
Valeria Calvi ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Platelet Function ◽  
Platelet Reactivity ◽  
The Elderly ◽  
Platelet Inhibition ◽  
Light Transmittance ◽  
Considerable Proportion ◽  
Old Patients ◽  
High Platelet Reactivity ◽  
Clopidogrel Therapy

SummaryStudies specifically designed to assess clopidogrel response in the elderly as well as treatment alternatives to improve platelet inhibition in this highrisk population are lacking. This study aimed to define phar-macodynamic (PD) profiles, including high platelet reactivity (HPR) rates, among elderly patients on maintenance clopidogrel therapy and to assess the PD effects of prasugrel 5 mg/day in elderly with HPR. This was a prospective observational PD study enrolling consecutive ≥75-year-old patients on maintenance clopidogrel therapy (75 mg/day) who were tested for clopidogrel response by the VerifyNow P2Y12 assay and light transmittance aggregometry (LTA). HPR rates were estimated using multiple definitions. HPR patients identified by the VerifyNow P2Y12 assay [P2Y12 reaction unit (PRU) ≥230] were switched to prasugrel 5 mg/day, and platelet function testing was performed after 15 days of treatment. PD testing was completed in 100 patients. The HPR prevalence varied between 25% and 32%, depending on the definition used. A PRU ≥230 was observed in 25 patients; of these, 20 switched to prasugrel 5 mg/day. This resulted in significant reduction in PRU mean values (279.8 ± 45.1 vs. 171.7 ± 65.2, p=0.0002) with an absolute between-treatment difference of 108.1 (95% confidence intervals 75.2–140.9). Accordingly, switching to prasugrel 5 mg/day overcame HPR in most (80%) patients. Consistently, all LTA measures were significantly lower after prasugrel compared with clopidogrel. In conclusion, a considerable proportion of elderly patients exhibit HPR while on standard clopidogrel therapy. Switching to 5 mg/day prasugrel in elderly patients with HPR is associated with enhanced platelet inhibition and overcomes HPR in the majority of these patients.

Effect of adjunctive dipyridamole to DAPT on platelet function profiles in stented patients with high platelet reactivity

2014 ◽  
Vol 112 (12) ◽  
pp. 1198-1208 ◽  
Author(s):  
Yongwhi Park ◽  
Udaya Tantry ◽  
Jong-Hwa Ahn ◽  
Kye Hwan Kim ◽  
Jin-Sin Koh ◽  
...  
Keyword(s):  
Platelet Function ◽  
Platelet Reactivity ◽  
Pde5 Inhibitor ◽  
Light Transmittance ◽  
Reactivity Index ◽  
Double Dose ◽  
High Platelet Reactivity ◽  
Number Of Patients ◽  
The Impact

SummaryAdjunctive use of phosphodiesterase (PDE) inhibitor can enhance antiplatelet and vasoprotective properties in patients with cardiovascular disease. The aim of this study was to evaluate the impact of PDE5 inhibitor dipyridamole on platelet function in stented patients with high platelet reactivity (HPR) during dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. Patients with HPR after 600-mg clopidogrel loading were randomly assigned to adjunctive dipyridamole 75 mg twice daily to standard DAPT (DIP group; n = 45) or double-dose clopidogrel of 150 mg daily (DOUBLE group; n = 46) for 30 days. Platelet function was assessed at baseline and 30-day follow-up with platelet reactivity index (PRI) by vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P) assay and platelet aggregation (PA) by light transmittance aggregometry (LTA). Primary endpoint was PRI at 30-day follow-up. HPR was defined as PRI > 50%. Baseline platelet function did not differ between the groups. Following 30-day therapy, platelet function was significantly reduced in the DIP and DOUBLE groups (all p-values ≤ 0.004 and ≤ 0.068, respectively). PRI values were not significantly different between the two groups (mean difference: 3.1%; 95% confidence interval: –2.8% to 9.0%: p = 0.295). PA values and prevalence of HPR were similar between the groups. However, a significant number of patients still exhibited HPR in the DIP (75.6%) and DOUBLE (67.4%) groups. In conclusion, among stented HPR patients, adding dipyridamole to DAPT does not reduce platelet reactivity and prevalence of HPR compared with double-dose clopidogrel therapy, and therefore both strategies are inadequate to overcome HPR.

Platelet Inhibition and Bleeding in Patients Undergoing Non-Cardiac Surgery—The BIANCA Observational Study

2018 ◽  
Vol 118 (05) ◽  
pp. 864-872 ◽  
Author(s):  
Elisabeth Mahla ◽  
Helfried Metzler ◽  
Helmar Bornemann-Cimenti ◽  
Florian Prueller ◽  
Reinhard Raggam ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Observational Study ◽  
Platelet Function ◽  
Platelet Reactivity ◽  
Objective Assessment ◽  
Timing Of Surgery ◽  
Light Transmittance ◽  
Reactivity Index ◽  
Multivariable Logistic Regression Analysis ◽  
Induced Aggregation

AbstractNearly 20% of patients will need non-cardiac surgery within 1 year of coronary stenting and their management is complicated by concomitant antiplatelet therapy. Platelet function testing may optimize the timing of surgery in these patients. In this prospective observational study, we explored the association between platelet reactivity and bleeding in patients undergoing non-cardiac surgery treated with clopidogrel with or without aspirin within 7 days before surgery. The timing of surgery was at the surgeon's discretion. Blood was drawn at induction of anaesthesia and platelet reactivity assessed by light transmittance aggregometry (LTA), vasodilator stimulated phosphoprotein (VASP) assay, Multiplate Analyzer and Innovance PFA-200. The primary endpoint was surgery-related thrombolysis in myocardial infarction (TIMI) bleeding. Among 197 patients enrolled, 72 and 12% underwent surgery within 24 and 48 hours of the last dose of clopidogrel, respectively. The median (interquartile range [IQR]) for pre-operative maximal adenosine diphosphate (ADP)-induced aggregation was 33.0% (21.0–57.5%), for VASP-platelet reactivity index was 61.5% (40.1–75.4%), for Multiplate was 22.0 (14.5–36.0) U*min and for Innovance PFA-200 was 224 (101.0–300.0) seconds. TIMI bleeding, observed in 25% of patients, decreased with increasing tertiles of platelet reactivity to ADP assessed by LTA (p = 0.031). Additionally, in a multivariable logistic regression analysis, platelet reactivity to ADP assessed by LTA was significantly associated with TIMI bleeding, as were age and urgency of surgery. These results demonstrate that in clopidogrel-treated patients, pre-operative platelet reactivity to ADP is associated with surgical bleeding risk. An objective assessment of pre-operative platelet function may optimize the timing of non-cardiac surgery in these patients.

Impact of adjunctive cilostazol therapy on platelet function profiles in patients with and without diabetes mellitus on aspirin and clopidogrel therapy

2011 ◽  
Vol 106 (08) ◽  
pp. 253-262 ◽  
Author(s):  
Dominick J. Angiolillo ◽  
Piera Capranzano ◽  
Jose Luis Ferreiro ◽  
Masafumi Ueno ◽  
Davide Capodanno ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Platelet Function ◽  
Thrombin Generation ◽  
Platelet Reactivity ◽  
Flow Cytometric Analysis ◽  
Light Transmittance ◽  
Reactivity Index ◽  
Pharmacodynamic Effects ◽  
Increased Risk ◽  
Clopidogrel Therapy

SummaryCilostazol is a platelet inhibitor which when added to aspirin and clopidogrel has shown to reduce the risk of recurrent ischaemic events without an increase in bleeding. These clinical benefits have shown to be more pronounced in patients with diabetes mellitus (DM). However, it remains unknown whether cilostazol exerts different pharmacodynamic effects in patients with and without DM. This was a randomised, double-blind, placebo-controlled, cross-over pharmacodynamic study comparing platelet function in patients with and without DM on aspirin and clopidogrel therapy. Patients (n=111) were randomly assigned to either cilostazol 100 mg or placebo twice daily for 14 days and afterwards crossed-over treatment for another 14 days. Platelet function was performed at baseline, 14 days post-randomisation, and 14 days post-cross-over. Functional testing to assess P2Y12 signalling included flow cytometric analysis of phosphorylation status of vasodilatorstimulated phosphoprotein measured by P2Y12 reactivity index (PRI), light transmittance aggregometry and VerifyNow. Thrombin generation processes were also studied using thrombelastography. Significantly lower PRI values were observed following treatment with cilostazol compared with placebo both in DM and non-DM groups (p < 0.0001). The absolute between-treatment differences of PRI between groups was a 35.1% lower in patients with DM (p=0.039). Similar results were obtained using all other functional measures assessing P2Y12 signalling. Thrombin generation was not affected by cilostazol. Cilostazol reduces platelet reactivity both in patients with and without DM, although these pharmacodynamic effects are enhanced in patients with DM. Despite the marked platelet inhibition, cilostazol does not alter thrombin-mediated haemostatic processes, which may explain its ischaemic benefit without the increased risk of bleeding.

Effect of Aspirin on the Thrombelastogram of Human Blood

1973 ◽  
Vol 30 (03) ◽  
pp. 494-498 ◽  
Author(s):  
G de Gaetano ◽  
J Vermylen
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Platelet Function ◽  
Human Blood ◽  
Platelet Rich Plasma ◽  
Plasma Samples ◽  
Release Reaction ◽  
Platelet Release

SummaryThrombelastograms of both native blood and re-calcified platelet-rich plasma samples taken from subjects given a single oral dose of aspirin (1 gram) were not significantly different from the pretreatment recordings. Aspirin also did not modify the thrombelastogram when preincubated in vitro with platelet-rich plasma at concentrations inhibiting the platelet “release reaction” by collagen. Thrombelastography therefore cannot evaluate the effect of aspirin on platelet function.

scholarly journals 2529

2017 ◽  
Vol 1 (S1) ◽  
pp. 67-67
Author(s):  
Dagmar Fredy Hernandez Suarez ◽  
Kyle Melin ◽  
Angel Lopez-Candales ◽  
Jorge Duconge
Keyword(s):  
Platelet Function ◽  
Clinical Characteristics ◽  
Platelet Reactivity ◽  
Artery Aneurysm ◽  
Multivariable Logistic Regression Analysis ◽  
Cross Sectional ◽  
Group I ◽  
Clopidogrel Therapy ◽  
Study Population ◽  
Artery Disease

OBJECTIVES/SPECIFIC AIMS: To determine the association between clinical characteristics and platelet reactivity in Hispanic patients on clopidogrel therapy. METHODS/STUDY POPULATION: A cross-sectional pilot study was performed in 58 Puerto Rican patients diagnosed with any type of vascular disease and actively receiving a maintenance dose of clopidogrel for at least 7 days. The study population was divided into 2 groups: Group I with non-high on-treatment platelet reactivity (TPR); Group II with high TPR. To determine the platelet function, P2Y12 reaction units (PRU) were obtained by VerifyNow® P2Y12 assay (Accumetrics, USA). RESULTS/ANTICIPATED RESULTS: We studied a heterogeneous cohort of patients with coronary artery disease (57%), peripheral artery disease (30%), carotid artery stenosis (7%), cerebral artery aneurysm (3%), and stroke (3%) on clopidogrel therapy for secondary prevention of thromboembolic events. The mean TPR was 205±49 PRU (range: 61–304), with a prevalence of 28% patients with high TPR (PRU≥230). No significant clinical differences were found between the non-high TPR and high-TPR groups (p>0.05). However, multivariable logistic regression analysis showed that both diabetes mellitus (OR=7.5; CI: 1.01–51.9) and proton-pump inhibitors (OR=13.6; CI: 1.3–142.0) were independently correlated with high TPR (p<0.05) after adjusting for other clinical variables. DISCUSSION/SIGNIFICANCE OF IMPACT: These results provide new insight into the importance of clinical characteristics on platelet reactivity in this Caribbean population. Further studies are warranted to determine whether important clopidogrel pharmacogenes are related with platelet function in Hispanics, as well as the role of TPR in guiding antiplatelet therapy and predicting future adverse cardiovascular events in this population.

The impact of renal function on platelet reactivity and clinical outcome in patients undergoing percutaneous coronary intervention with stenting

2014 ◽  
Vol 112 (12) ◽  
pp. 1174-1181 ◽  
Author(s):  
Nicoline Breet ◽  
Corine de Jong ◽  
Willem Jan Bos ◽  
Jochem van Werkum ◽  
Heleen Bouman ◽  
...  
Keyword(s):  
Renal Function ◽  
Antiplatelet Therapy ◽  
Platelet Function ◽  
Platelet Reactivity ◽  
Light Transmittance ◽  
Clinical Trial Registration ◽  
Platelet Function Test ◽  
Increased Risk ◽  
Function Test ◽  
The Impact

SummaryPatients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease. Previous studies have suggested that patients with CKD have less therapeutic benefit of antiplatelet therapy. However, the relation between renal function and platelet reactivity is still under debate. On-treatment platelet reactivity was determined in parallel by ADP- and AA-induced light transmittance aggregometry (LTA) and the VerifyNow® System (P2Y12 and Aspirin) in 988 patients on dual antiplatelet therapy, undergoing elective coronary stenting. Patients were divided into two groups according to the presence or absence of moderate/severe CKD (GFR<60 ml/min/1.73 m2). Furthermore, the incidence of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and stroke at one-year was evaluated. Patients with CKD (n=180) had significantly higher platelet reactivity, regardless of the platelet function test used. Patients with CKD more frequently had high on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) regardless of the platelet function test used. After adjustment for potential confounders, this was no longer significant. The event-rate was the highest in patients with both high on-treatment platelet reactivity (HPR) and CKD compared to those with neither high on-treatment platelet reactivity nor CKD. In conclusion, the magnitude of platelet reactivity as well as the incidence of HPR was higher in patients with CKD. However, since the incidence of HPR was similar after adjustment, a higher rate of co-morbidities in patients with CKD might be the major cause for this observation rather than CKD itself. CKD-patients with HCPR were at the highest risk of long-term cardiovascular events.Clinical Trial Registration: www.clinicaltrials.gov: NCT00352014.

Peri-operative platelet function testing: The potential for reducing ischaemic and bleeding risks

2011 ◽  
Vol 106 (08) ◽  
pp. 248-252 ◽  
Author(s):  
Paul A. Gurbel ◽  
Elisabeth Mahla ◽  
Udaya S. Tantry
Keyword(s):  
Platelet Function ◽  
Large Scale ◽  
Ex Vivo ◽  
Platelet Reactivity ◽  
Artery Bypass ◽  
Threshold Level ◽  
Platelet Inhibition ◽  
Bleeding Events ◽  
Atherothrombotic Event ◽  
Event Occurrence

SummaryThe pivotal role of platelet activation and reactivity during atherothrombotic event occurrence associated with acute coronary syndromes (ACS) or percutaneous coronary interventions (PCI) is well established. Numerous translational research studies have established a threshold level of platelet reactivity during dual antiplatelet therapy above which a higher risk for ischaemic event occurrence has been observed. The clinical validity of these threshold values in reducing ischemic event occurrence with modified P2Y12 receptor therapy is currently under investigation in large-scale clinical trials. The association between on-treatment platelet reactivity measured by an ex vivo assay and the occurrence of bleeding events is less established. Currently, there is limited evidence of an association between platelet inhibition and coronary artery bypass grafting (CABG)- related bleeding in patients on clopidogrel therapy indicating that preoperative platelet function monitoring may guide both the timing of elective CABG and the administration of blood products in patients needing surgery. However, in the absence of a large-scale prospective clinical trial, routine platelet function monitoring and modification of timing of surgery based on platelet function monitoring are currently not recommended.

Platelet reactivity in patients with aortic stenosis depends on LV-AO angle

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
P Mourikis ◽  
S Zako ◽  
L Dannenberg ◽  
R M'Pembele ◽  
T Hohlfeld ◽  
...  
Keyword(s):  
Aortic Stenosis ◽  
Platelet Activation ◽  
Platelet Function ◽  
Cox Regression ◽  
Light Transmission ◽  
Platelet Reactivity ◽  
Funding Source ◽  
Local Inflammation ◽  
German Research Foundation ◽  
Induced Aggregation

Abstract Background The pathogenesis of aortic stenosis (AS) is not fully understood. However, local inflammation of the valve appears to be a main player. Except haemostasis, platelets contribute to inflammatory processes in various ways. Furthermore, platelet function is altered in patients with AS. Moreover, a steep angle between the left ventricle and the aorta (LV-AO-angle) leads to turbulent blood flow. However, it is not known if platelet reactivity is associated with steep LV_AO angle in patients with AS. Methods We included 289 patients with severe AS and performed cardiac computertomography to assess the LV-AO-angle. Platelet function was evaluated by light transmission aggregometry by using collagen and adenosine-diphosphate to induce platelet activation Results ADP- and collagen induced aggregation showed a significant negative correlation with LV-AO-angle (ADP: r=−0.19, p=0.0009, R2=0.022; collagen: r=−0.21, p=0.0004, R2=0.027). ADP-induced MoA was significant higher in patients with a LV-AO-angle &lt;160° in comparison to patients with an angle ≥160° (&lt;160°: 66.99±20.72% vs. ≥160°: 60.66±19.85%, p=0.009). Collagen-induced platelet reactivity was significant higher in patients with a LV-AO-angle &lt;160° in comparison to patients with an angle ≥160° (&lt;160°: 78.67±13.19% vs. ≥160°: 73.85±14.44%, p=0.003). Multivariate cox-regression revealed that LV-AO angle &lt;160 was a robust predictor of ADP- and collagen-induced platelet aggregation Conclusion A steep LV-AO-angle is associated with enhanced platelet reactivity in patients with AS. Platelet activation is known to lead to local inflammation. Therefore, enhanced platelet reactivity could play crucial in the progression of AS. The clinical significance of a steep LV-AO-angle needs be evaluated in further trials. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): German Research Foundation

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