P2Y12 ADP Receptor Antagonist Research Articles

Effects of intravenous lysine acetylsalicylate versus oral aspirin on platelet responsiveness in patients with ST-segment elevation myocardial infarction

Abstract Background Prasugrel and ticagrelor, new P2Y12-ADP receptor antagonists, are associated with greater pharmacodynamic inhibition and reduction of cardiovascular events in patients with an acute coronary syndrome. However, evidence is lacked about the effects of achieving faster and stronger cyclooxygenase inhibition with intravenous lysine acetylsalicylate (LA) compared to oral aspirin on prasugrel inhibited platelets in patients with an ST-segment elevation myocardial infarction (STEMI). Methods This is a prospective, randomized, multicenter, open platelet function study conducted. STEMI patients were randomly assigned to receive a loading dose (LD) of intravenous LA 450mg plus oral ticagrelor 180mg, or LD of aspirin 300mg plus ticagrelor 180mg orally. Platelet function was evaluated at baseline, 30 min, 1h, and 24h using multiple electrode aggregometry and vasodilator-stimulated phosphoprotein phosphorylation (VASP). The primary endpoint of the study is the inhibition of platelet aggregation after arachidonic acid (AA) 1.5mM at 30 min. Secondary endopoints are the inhibition of platelet aggregation after AA baseline and at 1h, and 24h, and measurement of aggregation with other platelet test (ADP, collagen and VASP). Results A total of 32 STEMI patients were randomized (16 LA, 16 aspirin). The inhibition of platelet aggregation after AA 1.5 mM at 30 min was greater in subjects treated with LA compared with aspirin: 166 vs. 412 respectively, p=0.001. This differential effect was observed at 1 hour (p=0.01), but not at 24 hours. Subjects treated with LA presented less variability and faster and greater inhibition of platelet aggregation with AA compared with aspirin (Figure 1). Conclusions The administration of intravenous LA resulted in a significantly reduction of platelet reactivity compared to oral aspirin on ticagrelor inhibited platelets in patients with STEMI. Loading dose of LA achieves an earlier platelet inhibition, and with less variability than aspirin. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This study was supported by the CTU-SCReN (Clinical Trial Unit – Spanish Clinical Research Network) from San Carlos University Hospital (Madrid, Spain), financed by the ISCII (Project PI16/00191)

P2Y12-ADP Receptor Blockade in Chronic Kidney Disease Patients With Acute Coronary Syndromes.

Because of its high prevalence, chronic kidney disease (CKD) remains a major health hazard throughout the world. Patients with CKD have a high prevalence and incidence of acute coronary syndromes (ACS). Despite decades of improved care, their higher risk profile persists and cardiovascular diseases remain their leading cause of death. Along with the reduction of glomerular filtration rate, several physiological processes are impacted and participate in the pathophysiology of ischemic and bleeding events. CKD is associated with an accelerated and severe course of atherothrombotic disease, and this relates to a modified vascular milieu with alterations on the level of the coagulation cascade and platelet aggregation. In addition, pharmacokinetics of several drugs, in particular antithrombotics, are altered and differ from that of non-CKD patients. Patients with CKD therefore represent a challenging population for both physicians and researchers. In addition to these perturbations of physiological processes, CKD patients face 2 major issues. First, there is a clear gap in scientific research as they are commonly underrepresented or excluded from major clinical trials. This is particularly true regarding antithrombotic treatment during ACS. Second, there is a gap in offering evidence-based treatment for these patients including state-of-the art options for revascularization and modern antiplatelet treatment, both of which are commonly underused. During the last decade, new potent oral P2Y12-ADP receptor antagonists, prasugrel and ticagrelor, which are more potent antiplatelet agents compared with clopidogrel, were introduced for ACS treatment. However, despite the fact that CKD patients represent a large proportion of those experiencing an ACS and are considered at high risk, there is a lack of dedicated trials and we are left with subgroup analysis of large randomized clinical trials were stage 4 and dialysis patients were rare. In the present review we summarize the mechanisms involved in the high ischemic and bleeding risk of CKD patients and the risk-benefit ratio of potent antiplatelet drugs during ACS.

Early versus delayed invasive strategy for intermediate- and high-risk acute coronary syndromes managed without P2Y12 receptor inhibitor pretreatment: Design and rationale of the EARLY randomized trial.

According to recent literature, pretreatment with a P2Y12 ADP receptor antagonist before coronary angiography appears no longer suitable in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) due to an unfavorable risk-benefit ratio. Optimal delay of the invasive strategy in this specific context is unknown. We hypothesize that without P2Y12 ADP receptor antagonist pretreatment, a very early invasive strategy may be beneficial. The EARLY trial (Early or Delayed Revascularization for Intermediate- and High-Risk Non-ST-Segment Elevation Acute Coronary Syndromes?) is a prospective, multicenter, randomized, controlled, open-label, 2-parallel-group study that plans to enroll 740 patients. Patients are eligible if the diagnosis of intermediate- or high-risk NSTE-ACS is made and an invasive strategy intended. Patients are randomized in a 1:1 ratio. In the control group, a delayed strategy is adopted, with the coronary angiography taking place between 12 and 72 hours after randomization. In the experimental group, a very early invasive strategy is performed within 2 hours. A loading dose of a P2Y12 ADP receptor antagonist is given at the time of intervention in both groups. Recruitment began in September 2016 (n = 558 patients as of October 2017). The primary endpoint is the composite of cardiovascular death and recurrent ischemic events at 1 month. The EARLY trial aims to demonstrate the superiority of a very early invasive strategy compared with a delayed strategy in intermediate- and high-risk NSTE-ACS patients managed without P2Y12 ADP receptor antagonist pretreatment.

The Impact of Antiplatelet Treatment on Endothelial Function.

The vascular endothelium comprises a continuous single cell layer of endothelial cells which line the entire cardiovascular system. Impaired endothelial function underlies the pathogenesis and contributes to the progression of atherosclerosis. Oxidative stress, vasoconstriction, inflammation, proliferation and thrombosis occur in dysfunctional endothelium while the latter, is primarily mediated by platelet activation and adherence to vascular wall. Despite the primary action of antiplatelet agents including aspirin, P2Y12 ADP receptor antagonists and glycoprotein IIb/IIIa inhibitors, a growing body of literature suggests that an important mechanism of their action involves complex modulation of endothelial function via platelet-endothelial interactions, modification of the inflammatory cytokine cascade and nitric oxide mediated effects. These agents represent the mainstay in pharmacological treatment of all aspects of cardiovascular disease both in primary and secondary prevention. However beyond these properties, it is important to note that pharmacological modification of endothelial dysfunction has been postulated as a therapeutic target for reduction of cardiovascular events.

Platelet reactivity in patients receiving a maintenance dose of P2Y12-ADP receptor antagonists undergoing elective percutaneous coronary intervention

BackgroundP2Y12-ADP receptor blockade during percutaneous coronary intervention (PCI) is critical to prevent thrombotic events. In patients under chronic P2Y12 blockers, the use of additional loading dose (LD) before an elective PCI is debated. We aimed to investigate the rate of high on-treatment platelet reactivity (HTPR) in patients undergoing elective PCI during chronic clopidogrel or ticagrelor therapy. Methods and resultsWe performed a sub-group analysis of a randomized trial comparing ticagrelor and clopidogrel in acute coronary syndrome (ACS) patients undergoing PCI. Multi-vessel disease patients requiring a staged PCI one month after the ACS were included. The VASP (vasodilatatory phosphoprotein) index, which is a specific and reproducible platelet assay to measure P2Y12-ADP receptor activity, was used to assess the biological efficacy of the maintenance dose (MD) of ticagrelor and clopidogrel before PCI. Forty-one patients in each group of randomization required a staged PCI. They were similar regarding the baseline demographic, clinical and angiographic characteristics. The mean VASP index in the ticagrelor group was 20.7±8.8% compared to 51.8±17% in the clopidogrel group (p<0.001) before PCI. No patients had a VASP index ≥50% in the ticagrelor group compared to 56% in the clopidogrel group (p<0.001). Following PCI the rate of peri-procedural MI was higher in the clopidogrel group (p=0.02). ConclusionsUnlike clopidogrel MD, ticagrelor MD achieves an optimal PR inhibition in all patients during a staged PCI.

P2Y12 receptor inhibition and LPS-induced coagulation.

Platelets play a major role in the complex interactions involved in blood coagulation via multiple mechanisms. As reported in this issue, Schoergenhofer et al. tested the hypothesis that platelet inhibition by prasugrel, a potent platelet P2Y12 ADP receptor antagonist, attenuates the effect of lipopolysaccharide (LPS) on the blood coagulation system in healthy human subjects. LPS, a bacterial product with potent pro-inflammatory and pro-thrombotic effects, plays a central role in sepsis. It activates monocytes and endothelial cells via Toll-like receptor (TLR) 4 and other TLRs to stimulate production of TF and other pro-coagulant molecules, chemokines and cytokines. Treatment with prasugrel did not decrease biomarkers of coagulaion. A better understanding of the relative roles of platelet and coagulation mechanisms in triggering the pro-thrombotic state may lead to more effective antithrombotic strategies.

P2Y12-ADP receptor antagonists: Days of future and past.

Antiplatelet therapy is the cornerstone of the therapeutic arsenal in coronary artery disease. Thanks to a better understanding in physiology, pharmacology and pharmacogenomics huge progress were made in the field of platelet reactivity inhibition thus allowing the expansion of percutaneous coronary intervention. Stent implantation requires the combination of two antiplatelet agents acting in a synergistic way. Asprin inhibit the cyclo-oxygenase pathway of platelet activation while clopidogrel is a P2Y12 adenosine diphosphate (ADP)-receptor antagonist. This dual antiplatelet therapy has dramatically improved the prognosis of stented patients. However, due to pharmacological limitations of clopidogrel (interindividual variability in its biological efficacy, slow onset of action, mild platelet reactivity inhibition) ischemic recurrences remained high following stent implantation especially in acute coronary syndrome patients. Thus, more potent P2Y12-ADP receptor inhibitors were developped including prasugrel, ticagrelor and more recently cangrelor to overcome these pitfalls. These new agents reduced the rate of thrombotic events in acute coronary syndrome patients at the cost of an increased bleeding risk. The abundance in antiplatelet agents allow us to tailor our strategy based on the thrombotic/bleeding profile of each patient. Recently, the ACCOAST trial cast a doubt on the benefit of pre treatment in non-ST segment elevation acute coronary syndrome. The aim of the present review is to summarize the results of the main studies dealing with antiplatelet therapy in stented/acute coronary syndromes patients.

Abstract 15265: Clopidogrel Response Variability is Associated With Endothelial Dysfunction in Coronary Artery Disease Patients Receiving Dual Antiplatelet Therapy

Introduction: Dual antiplatelet therapy with aspirin and a platelet P2Y12 ADP receptor antagonist is the cornerstone of treatment following percutaneous coronary intervention (PCI). Several clinical and genetic factors can cause suboptimal clopidogrel response. Hypothesis: Endothelial dysfunction affects clopidogrel response variability in subjects with stable coronary artery disease (CAD) after PCI. Methods: We consecutively enrolled 198 patients with stable CAD one month after successful PCI. All patients were receiving dual antiplatelet therapy (clopidogrel 75mg and aspirin 100mg/day). Platelet reactivity was measured by VerifyNow P2Y12 assay (Accumetrics, San Diego, CA). VerifyNow reports its results in P2Y12 reaction units (PRU) and the diagnostic cut-off value is 230. Endothelial function was evaluated by flow mediated dilation (FMD). Results: Patients with high on treatment platelet reactivity (32% of the study population), compared to subjects with low on treatment platelet reactivity, presented decreased FMD (4.35±2.22% vs. 5.74±3.29%, p=0.01). Moreover, an inverse association between endothelial function measurement and platelet reactivity (r=-0.24, p=0.001) was founded. Importantly, multivariate analysis after adjustment for age, gender and confounders revealed by the univariate analysis (left ventricle ejection fraction, body mass index, coronary lesion number) revealed that for every decrease in FMD by 1% there is an anticipated increased in P2Y12 reactive units by 10 units [b=-9.9, 95%CI(-19.0, -0.7), p=0.04]. Conclusions: Endothelial dysfunction is associated with clopidogrel response variability in patients after PCI receiving dual antiplatelet therapy. These findings shed some light on the mechanisms affecting individual platelet response to antiplatelet therapy and may explain the non-straight forward association between clopidogrel dose, platelet inhibition and cardiovascular outcome.

Abstract 177: Ticagrelor, but not Clopidogrel, Protects the Heart Against Reperfusion Injury and Improves Remodeling After Myocardial Infarction

Background: Clopidogrel (C) and Ticagrelor (T) are P2Y12 ADP receptor antagonists. In addition, ticagrelor inhibits adenosine cell uptake. In PLATO trial T reduced the incidence of the primary composite endpoint myocardial infarction, stroke or cardiovascular death over C in patients with acute coronary syndromes. Previous data show that 7d pretreatment with T limits infarct size (IS) in rats. We compared the effects of C and T, administered just before reperfusion on IS. We also assessed the effect of T and C, administered just before reperfusion and/or 6w oral treatment on cardiac remodeling. Methods: Rats underwent 30min coronary artery ligation. 1) At 25min of ischemia rats received intraperitoneal (IP) vehicle, T (10 or 30mg/kg), or C (12.5mg/kg). Area at risk (AR) was assessed by blue dye and IS by TTC staining 24h after reperfusion. 2) Rats received vehicle without (sham) or with (control) coronary ischemia, T (30mg/kg) IP (TIP), T (300mg/kg/d) oral for 6w, started a day after reperfusion (TPO), TIP+PO (TIPPO), or C (12.5mg/kg IP +62.5mg/kg/d PO for 6w). LV dimensions and function was assessed by echo at 6w. Results: 1) AR was comparable among groups. IS was 45.3±1.7% of the AR in the control group. T10 (31.5±1.8%; p=0.001) and T30 (21.4±2.6% p&lt;0.001) significantly reduced IS, whereas C (42.4±2.6%) had no effect. Platelet aggregation in the controls was 64.7±1.3% and was comparable in T30 (24.9±1.8%) and C (23.2±1.8%) at 2h post reperfusion. T30 increased Akt, eNOS and ER1/2 phosphorylation 4h after reperfusion, whereas C had no effect. 2) Platelet aggregation at 1w oral treatment was 59.7±3.2% in the control group and was comparable in TIPPO (18.1±1.3%) and C (17.4±0.7%). Left ventricular ejection fraction was 77.6±0.9%*, 44.8±3.5%, 69.5±1.6%*, 69.2±1.0%*, 76.3±1.2%*, and 37.4±3.7% in the sham, vehicle, TIP, TPO, TIPPO and C treated group, respectively (*p&lt;0.001 vs. vehicle). Left ventricular diameters at diastole and systole showed the same pattern. Conclusions: T, but not C, administered just before reperfusion protects against reperfusion injury. Oral T (in combination or not with acute treatment just before reperfusion) treatment for 6w improves heart function. C, despite achieving similar degree of platelet inhibition had no effect on remodeling.

COMparison of Platelet reactivity following prAsugrel and ticagrelor loading dose in ST-Segment elevation myocardial infarctION patients: The COMPASSION study

Prasugrel and ticagrelor are potent P2Y12-ADP receptor antagonists which are superior to clopidogrel in acute coronary syndromes. To date no clinical trial directly compared these two drugs. Platelet reactivity correlates with ischemic and bleeding events in patients undergoing percutaneous coronary intervention. Recent pharmacological studies have observed a delayed onset of action of these two drugs in ST-segment elevation myocardial infarction (STEMI). We provide the first adequately powered pharmacological study comparing PR following ticagrelor and prasugrel loading dose (LD) in STEMI patients when the maximal biological effect is reached. In the present study, ticagrelor was associated with a lower rate of high on-treatment PR compared to prasugrel.

Consensus recommendations for using the Multiplate(®) for platelet function monitoring before cardiac surgery.

Patients requiring urgent cardiac surgery are usually already taking antiplatelet drugs including aspirin and a P2Y12 ADP receptor antagonist (e.g., clopidogrel, prasugrel or ticagrelor). This presents clinicians with the challenge of balancing the risk of thrombotic complications, if antiplatelet drugs are stopped before surgery, with the problems of excessive bleeding when surgery is performed in the absence of adequate platelet function. Preoperative platelet function monitoring is able to identify when patients have recovered platelet function. The Multiplate(®) (multiple electrode impedance platelet aggregometer) is a point of care device that enables monitoring of platelet function. The authors offer recommendations based on real-world, collective experience in the use of platelet function monitoring. These cover the use of the Multiplate(®) analyser to predict the need for platelet transfusion in the perioperative period and the individualized waiting period after cessation of P2Y12 ADP receptor antagonists before cardiac surgery.

Platelet reactivity evaluated with the VASP assay following ticagrelor loading dose in acute coronary syndrome patients undergoing percutaneous coronary intervention

BackgroundThe level of platelet reactivity (PR) inhibition obtained after P2Y12-ADP receptor antagonist loading dose (LD) is associated with the ischemic and bleeding risk following percutaneous coronary intervention (PCI) in acute coronary syndromes (ACS). ObjectiveWe aimed to evaluate the level of PR inhibition achieved by a 180mg LD of ticagrelor and the rate of high on-treatment platelet reactivity (HTPR) in ACS patients undergoing PCI. MethodsWe performed a multicentre prospective observational study enrolling ACS patients undergoing PCI. Patients were included if they were admitted for ST-elevation myocardial infarction or non ST-elevation ACS. To assess PR, a VASP index was measured at least 6 and within 24hours following a 180mg LD of ticagrelor. HTPR was defined as a VASP index ≥50%. ResultsOne hundred and fifteen patients were included: 31.3% of STEMI, 49.6% of NSTEMI and 19.1% of unstable angina. Following ticagrelor LD the mean VASP index was 17±14%. However the response to ticagrelor was not uniform with a small inter-individual variability: inter quartile range: 7.6–22.8% and a rate of HTPR of 3.5%. A high number of patients, 65.6%, had a VASP index <16%. None of the baseline characteristics of the study population was associated with PR. In addition, PR was similar in STEMI, NSTEMI and unstable angina (p=0.9). ConclusionIn ACS patients the level of PR inhibition achieved by a 180mg loading dose of ticagrelor is not uniform and the rate of HTPR is 3.5%. A high proportion of patients exhibited a VASP index <16%.

Insufficient Efficiency of Prasugrel in Diabetic Patients with Acute STEMI Undergoing Ppci of Culprit Coronary Lesion – Review of Current Knowledge

The activation and subsequent platelet aggregation plays a key role in the formation of arterial thrombosis and therefore is the key therapeutic target in the treatment of acute coronary syndromes. Dual antiplatelet therapy containing aspirin and P2Y12 ADP receptor antagonist forms currently the basis in acute ST – elevation myocardial infarction (STEMI) pharmacological treatment. Nevertheless, there is a wide variability in pharmacodynamic response to administration of clopidogrel, the most frequently used P2Y12 ADP receptor antagonist. High platelet reactivity after clopidogrel administration is associated with increased risk of in - stent thrombosis and points to the suitability of laboratory monitoring of antiplatelet therapy effectivity in clinical practice. Laboratory monitoring of antiplatelet therapy by ex vivo platelet function tests may help to identify individuals with poor antiplatlet response. Recently, there is growing number of data reporting a failure in antiplatelet response following clopidogrel administration, which is specifically associated with insulin resistance and diabetes mellitus. Prasugrel, a new, potent P2Y12 ADP receptor antagonist, provides faster and more consistent inhibition of platelet function compared with clopidogrel. Prasugrel therapy was repeatedly described as an effective method to overcome clopidogrel resistance and prasugrel resistance has not yet been reliably described. Article gives a review about prasugrel resistance and its role in acute coronary syndrome patients.

Tailoring Antiplatelet Therapy: A Step Toward Individualized Therapy to Improve Clinical Outcome?

P2Y12 adenosine di-phosphate (ADP) receptor antagonists are critical to reduce thrombotic recurrences in acute coronary syndromes patients and for those undergoing percutaneous coronary revascularization. Multiple lines of evidence suggest that the level of on-treatment platelet reactivity inhibition with P2Y12 ADP receptor antagonists correlates with thrombotic recurrences. Recent studies observed a relationship between excessive platelet reactivity inhibition and bleedings. Together these data support the potential of platelet reactivity measurement to prevent thrombotic events without increasing bleeding. In the present review we aimed to summarize evidences of a therapeutic window for P2Y12-ADP receptor antagonists and the potential of platelet reactivity monitoring and individualized antiplatelet therapy to optimize the clinical outcome in patients suffering from an acute coronary syndrome or undergoing percutaneous coronary intervention.

Biomarkers of Hemostatic Activation in a Randomized, Double-Blind, Phase 2 Study of Prasugrel Compared to Placebo in Adults with Sickle Cell Disease

Abstract 2127 Introduction:Activation of the hemostatic cascade and platelet activation in particular, has been implicated in the pathogenesis of sickle cell disease (SCD). Prasugrel is a third generation thienopyridine antiplatelet agent, an oral P2Y12 ADP receptor antagonist that is FDA-approved for use in patients with acute coronary syndromes undergoing percutaneous coronary revascularization. We evaluated serial biomarkers of hemostatic activation from a trial of prasugrel in adult patients with SCD. Methods:This was a multicenter, randomized, double-blind phase 2 adaptive study design with a 2:1 prasugrel:placebo ratio. Study drug, prasugrel 5 mg or placebo, was given once daily for 30 days. The primary endpoint was safety as measured by hemorrhagic events requiring medical attention. Samples for biomarkers were collected prior to initiation of study drug, on day 10 ± 2, and on day 30 ± 3. Multi-color fluorescent activated cell sorting and monoclonal antibodies were used to determine platelet P-selectin expression, platelet-monocyte aggregates (PMA), and platelet-neutrophil aggregates (PNA) using previously published protocols. Soluble P-selectin (sP-selectin), soluble CD40 ligand (sCD40L), thromboxane B2 (serum TXB2), and prothrombin fragment F1.2 (F1.2) were determined using standard enzyme-linked immunoassays. Statistical comparison between prasugrel and placebo was performed using a mixed model with treatment, baseline measurement, genotype of SCD, visit and the interaction between visit and treatment as fixed effects and subjects as a random effect. Results:Forty-one patients were randomized to prasugrel 5 mg and 21 to placebo. Mean age was 32 years; 48% were female; 60% HbSS, 5% HbS/b0thalassemia, 10% HbS/b+thalassemia, and 24% HbSC (1 patient was found not to have SCD but to only have b-thalassemia trait). Eighteen patients in the prasugrel and 9 in the placebo arm were on hydroxyurea prior to study drug. Results are shown in the Figure. Compared to placebo, platelet P-selectin (unstimulated), sP-selectin, and sCD40L all achieved or approached significantly lower values in the prasugrel group on day 10 and 30, as did ADP-stimulated platelet P-selectin values (data not shown). TXB2 was significantly lower on day 10 but not on day 30 (Fig. 1), as were PMA/PNA unstimulated, and PMA/PNA in response to ADP ex vivo. F1.2 levels were not different between the groups at either day 10 or 30 (data not shown). Conclusions:As would be predicted by the mechanism of action, prasugrel resulted in decreased cellular and soluble biomarkers of platelet activation. There was no effect on coagulation as assessed by F1.2, a marker of thrombin generation. Clinical results reported elsewhere suggest a decrease in pain rate. Prasugrel 5 mg po daily clearly decreases markers of platelet activation in adult SCD patients. These biomarkers can be incorporated in future studies of prasugrel in SCD to correlate with clinical outcomes. [Display omitted] Disclosures:Wun:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Knupp:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. McMahon:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Strouse:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Heath:Eli Lilly and Company: Employment, Equity Ownership. Nwachuku:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Riesmeyer:Eli Lilly and Company: Employment, Equity Ownership.

A Randomized, Double-Blind, Adaptive Phase 2 Multi-Center Study of Prasugrel Compared to Placebo in Adults with Sickle Cell Disease

Abstract 847▪FN2▪This icon denotes a clinically relevant abstract Introduction:Platelet activation may play a role in the pathogenesis of various complications related to sickle cell disease (SCD). Older studies of antiplatelet agents in reducing the frequency and severity of pain in SCD have been inconclusive. Prasugrel is a third generation thienopyridine antiplatelet agent, an oral P2Y12 ADP receptor antagonist that is FDA-approved for use in patients with acute coronary syndrome undergoing percutaneous coronary intervention. We undertook a study to determine the safety, pharmacodynamics and possible efficacy of prasugrel in adult patients with SCD. Methods:This was a multicenter, randomized, double-blind phase 2 adaptive study design with a 2:1 prasugrel:placebo randomization ratio. Study drug was given once daily for 30 days. The primary endpoint was safety as measured by hemorrhagic events requiring medical attention. Secondary endpoints included pain frequency and severity assessed by pain diary and pharmacodynamic effects measured by VerifyNow” P2Y12 reactivity units (VN PRU) and vasodilator stimulated phosphoprotein (VASP) phosphorylation platelet reactivity index (PRI). If interim analysis of pharmacodynamic data revealed insufficient platelet inhibition in the first 16 patients randomized to 5 mg daily prasugrel, the dose was to be escalated to 7.5 mg. Results:Forty-one patients were randomized to the prasugrel arm and 21 to placebo. Mean age was 32 years; 48% were female; 60% HbSS, 5% HbS/b0thalassemia, 10% HbS/b+thalassemia, and 24% HbSC (1 patient was found not to have SCD but to only have b-thalassemia trait). Eighteen patients (44%) in the prasugrel and 9 (43%) in the placebo arm were on hydroxyurea prior to study drug initiation. These characteristics were balanced between the treatment arms, as was baseline pain intensity (average pain score on a scale of 0 to 9 over 7 days prior to study drug). No hemorrhagic event required medical attention. Eight (20%) of patients in the prasugrel arm had hemorrhagic adverse events of which 6 (15%) were possibly related to study drug versus 1 (5%) in the placebo arm; all were mild except one moderate menorrhagia in a prasugrel-treated patient. There were numerical decreases in median and mean pain rate (% of days with pain) and intensity in the prasugrel arm compared to placebo but this did not reach statistical significance (Figure 1). The proportion of pain episodes requiring medical attention was also numerically lower: 23% prasugrel versus 37% placebo. There was measurable platelet inhibition as assessed by both VerifyNow” PRU and VASP PRI such that no dose escalation was necessary (Figure 2). [Display omitted] [Display omitted] Conclusions:Prasugrel, 5 mg once daily for 30 days, had anticipated pharmacodynamic effect on platelets in adult patients with SCD, was well tolerated, and was not associated with serious hemorrhagic events. Despite the small size and short duration of this phase 2 study, there was a suggestion of decreased days with pain. These data provide a rationale for a Phase 3 study of prasugrel adequately powered to determine effects on relevant clinical outcomes such as pain rate, severity, and frequency of vaso-occlusive crisis. Disclosures:Wun:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Krishnamurti:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Kutlar:Celgene: Research Funding; Novartis: Research Funding; Hemaquest: Research Funding; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Ataga:Adventrx: Consultancy; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Heath:Eli Lilly and Company: Employment, Equity Ownership. Nwachuku:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Riesmeyer:Eli Lilly and Company: Employment, Equity Ownership.

A Phase 1 Study of Prasugrel in Subjects with Sickle Cell Disease: Impact on Ex Vivo Platelet Reactivity

Abstract 1053 Introduction:There is evidence of increased platelet reactivity in subjects with sickle cell disease (SCD). This could contribute to vaso-occlusive complications that characterize the disease; thus, antiplatelet therapy may be useful in the management of SCD. Prasugrel, a novel thienopyridine P2Y12 ADP receptor antagonist, is an effective inhibitor of ADP-mediated platelet activation and aggregation, but it has not been evaluated in SCD. The present study examined 1) the utility of various platelet assays used to assess platelet reactivity in blood from subjects with SCD; and 2) the impact of prasugrel on platelet reactivity in subjects with SCD compared to healthy controls. Methods:Twenty-six adult subjects were enrolled and 25 completed the study: 12 with SCD and 13 well-matched healthy controls. Subjects were examined before and after 12±2 days of treatment with oral prasugrel (5.0 mg/day for subjects weighing <60 kg and 7.5 mg/day for subjects weighing ≥60 kg). Platelet reactivity to ADP at baseline and after 12 days of prasugrel treatment was assessed by 1) maximum platelet aggregation (MPA) to 5mM ADP using light transmission aggregometry (LTA); 2) area under the aggregation curve (AU.min) to 6.5 mM ADP using impedance aggregometry (IA); 3) P2Y12 reactivity units (PRU) by VerifyNow P2Y12 (VN); and 4) platelet reactivity index (PRI) by vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Baseline population differences and the within-group changes from baseline were analyzed using t-tests. The population differences for change from baseline were analyzed using an analysis of covariance model, with dose, subject group, and dose-by-subject group interaction as fixed effects, and baseline measurement as the covariate. Results:All data are shown as mean±SD. At baseline and prior to initiation of prasugrel, subjects with SCD showed increased platelet reactivity vs. healthy controls, as evidenced by VN (PRU: 407.9±39.6 vs. 322.5±74.2, p=0.003) and IA (AU.min: 106.4±27.9 vs. 76.5±13.2, p=0.002). However, there was no difference between subjects with SCD and healthy controls in baseline platelet reactivity with LTA (MPA: 73.1±14.4% vs. 80.4±23.2%, p=0.376). Baseline PRI by VASP was significantly lower in subjects with SCD than in healthy controls (PRI: 59.4±23.3% vs. 78.9±10.0%, p=0.018) (Figure).After 12 days of treatment with prasugrel, all measures of platelet reactivity were significantly reduced compared with baseline in both SCD subjects and healthy controls (p< 0.05 for each assay); absolute change from baseline were as follows: LTA (−33.4 vs. −49.9), IA (−63.2 vs. −49.5), VN (−197.4 vs. −212.0), and VASP (−46.0 vs. −49.9; all SCD vs. control respectively, Figure). Changes from baseline in subjects with SCD compared to changes from baseline in healthy controls were not statistically significant after adjusting for baseline.Prasugrel was safe and well tolerated with no serious adverse events observed during the study. No subject discontinued the study due to an adverse event (AE) and the majority of AEs were mild. No subjects with SCD reported any bleeding-related AEs. Conclusion:At baseline, compared with healthy controls, subjects with SCD had increased platelet aggregation to ADP in whole blood by two independent assays (VN and IA), but similar aggregation in platelet-rich plasma (LTA). These results may be influenced by the lower hematocrit and higher platelet count in subjects with SCD. At baseline, subjects with SCD had more variable VASP PRI values resulting in reduced mean PRI. It remains to be determined whether this is a reflection of altered ADP and/or PGE1 signaling in certain individuals with SCD. Prasugrel administration significantly attenuated ADP-stimulated platelet reactivity in SCD subjects as measured by LTA, IA, VN, and VASP. The extent of prasugrel inhibition of platelet function in SCD was similar to that observed in prasugrel-treated healthy controls as measured by all 4 assays. The present results demonstrate that prasugrel inhibits platelet function in subjects with SCD, and that this inhibition can be monitored by a variety of assays. These results provide the basis for future studies evaluating prasugrel for the treatment of vascular complications associated with SCD. [Display omitted] p value: change from baseline; error bars: arithmetic mean±SD for combined dose data Disclosures:Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Small:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Lachno:Eli Lilly and Company: Employment, Equity Ownership. Frelinger:Takeda: Research Funding; GLSynthesis: Research Funding; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Consultancy, Research Funding. Howard:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Payne:Eli Lilly and Company: Employment, Equity Ownership.

Le ticagrelor dans les syndromes coronaires aigus : résultats de l’étude PLATO

Antiplatelet agents are critical in the care of acute coronary syndromes and percutaneous coronary interventions. Clopidogrel was for several years the gold standard; the development of new agents overcoming its main limitations in terms of intensity and onset of action enable a decrease in the rate of recurrent thrombotic events. Ticagrelor is a new P2Y12-ADP receptor antagonist which, unlike clopidogrel and prasugrel, which are thienopyridines, is a reversible agent and has an original mechanism of action. The goal of the present review is to summarize published data on this new-agent which will soon be available for daily clinical practice.

Poly-N-Acetyl Glucosamine Fibers Induce Angiogenesis in ADP Inhibitor-Treated Diabetic Mice

It has been previously demonstrated that short-fiber poly-N-acetyl-glucosamine (sNAG) nanofibers specifically interact with platelets, are hemostatic, and stimulate diabetic wound healing by activating angiogenesis, cell proliferation, and reepithelialization. Platelets play a significant physiologic role in wound healing. The influence of altered platelet function by treatment with the ADP inhibitor Clopidogrel (CL) on wound healing and the ability of sNAG to repair wounds in diabetic mice treated with CL were studied. Dorsal 1 cm2 skin wounds were excised on genetically diabetic 8-week to 12-week-old, Lep/r-db/db male mice, and wound healing kinetics were determined. Microscopic analysis was performed for angiogenesis (PECAM-1) and cell proliferation (Ki67). Mice were either treated with CL (P2Y12 ADP receptor antagonist, CL) or saline solution (NT). CL wounds were also treated with either a single application of topical sNAG (CL-sNAG) or were left untreated (CL-NT). CL treatment did not alter wound healing kinetics, while sNAG induced faster wound closure in CL-treated mice compared with controls. CL treatment of diabetic mice caused an augmentation of cell proliferation and reduced angiogenesis compared with nontreated wounds. However, sNAG reversed the effects of CL on angiogenesis and partially reversed the effect on cell proliferation in the wound beds. The sNAG-treated wounds in CL-treated mice showed higher levels of cell proliferation and not did inhibit angiogenesis. CL treatment of diabetic mice decreased angiogenesis and increased cell proliferation in wounds but did not influence macroscopic wound healing kinetics. sNAG treatment did not inhibit angiogenesis in CL-treated mice and induced faster wound closure; sNAG technology is a promising strategy to facilitate the healing of complex bleeding wounds in CL-treated diabetic patients.

Genotypic and Phenotypic Assessment of Platelet Function and Response to P2Y12 Antagonists

The P2Y12-ADP receptor antagonists are the cornerstone of oral antiplatelet therapy in the secondary prevention of coronary artery disease, especially after acute coronary syndrome or percutaneous coronary intervention. Currently, the therapeutic agents available to block the receptor include clopidogrel and prasugrel; ticagrelor is not available everywhere. Clopidogrel was the gold standard, but recently it has been challenged by prasugrel and ticagrelor. One pitfall of clopidogrel is that in some patients it cannot induce optimal platelet reactivity inhibition in connection with several factors, including some genetic polymorphisms of enzymes participating in its bioabsorption or metabolism. This variability of response can be evaluated by platelet reactivity monitoring. This comprehensive review provides the available data regarding the genotypic and phenotypic interaction with the response to P2Y12-ADP receptor antagonists and discusses the concept of personalized antiplatelet therapy based on a genotypic or phenotypic profile.