Platelet P2Y12 Research Articles

Cangrelor and Heparin for Left Ventricular Assist Device Implantation in a Patient with Heparin-Induced Thrombocytopenia

Introduction Perioperative anticoagulation in patients with heparin-induced thrombocytopenia (HIT) requiring cardiopulmonary bypass (CPB) presents a clinical challenge due to high risk of intravascular thrombosis. Alternative anticoagulants have been used but carry their own risks. We report the successful use of Cangrelor, a P2Y12 platelet receptor antagonist, with heparin during left ventricular assist device (LVAD) implantation. Case Report A 25-year-old female with dilated cardiomyopathy due to dermatomyositis and Turner's syndrome and left ventricular thrombus on apixaban, was admitted to our institution with worsening dyspnea. She had a left lower lobe segmental and subsegmental pulmonary embolus and was started on heparin infusion. Over a few days, her platelet count decreased from 278K to 8K and she developed a subclavian and internal jugular deep vein thrombosis. Given concern for HIT, she was switched to bivalirudin. Severe HIT was confirmed with an optical density of 2.8. She progressed into cardiogenic shock requiring inotrope and mechanical support. Given her hemodynamic deterioration, we proceeded with HeartMate II LVAD implant after thorough evaluation. In consultation with hematology, we utilized cangrelor and heparin to minimize platelet aggregation and thrombosis during CPB. Cangrelor has a favorable pharmacokinetic profile for use with heparin in HIT patients given its fast-onset, short half-life, and high-affinity causing aggregation. Intraoperatively, platelet reactivity units (PRUs) were measured to assess Cangrelor's activity and ensure P2Y12 antiplatelet effect with the appropriate scale. A cangrelor bolus and infusion were given before heparinization; PRU reduced from 326 to 103 (less than 208 indicates presence of antiplatelet effect). Systemic heparinization was then safely achieved with Cangrelor infusion being discontinued 10 minutes prior to heparin reversal with protamine. She was started on bivalirudin postoperatively and eventually transitioned to coumadin. Summary This case represents a novel approach of using cangrelor with heparin intraoperatively for a patient with confirmed HIT requiring urgent LVAD implantation. Cangrelor use with heparin offers a safe and effective option in surgeries requiring CPB while minimizing hematologic complications of thrombosis and bleeding.

Effects of clopidogrel, prasugrel and ticagrelor on prevention of stent thrombosis in patients underwent percutaneous coronary intervention: A network meta-analysis.

BackgroundClopidogrel, prasugrel and ticagrelor, acting on platelet P2Y12 receptor, are commonly used for prevention of stent thrombosis (ST) among patients who underwent percutaneous coronary intervention (PCI). This study aimed to compare the effects of these drugs by a systematic review and network meta‐analysis.HypothesisEfficacies of clopidogrel, prasugrel and ticagrelor on preventing ST are not the same.MethodsPubMed, Embase and Cochrane Library were searched for randomized controlled trials (RCTs) that investigated the effect of clopidogrel, prasugrel, or ticagrelor on prevention of ST in patients who underwent PCI. The efficacies between groups were compared by a Bayesian network meta‐analysis, by which the pooled odds ratios (ORs) and 95% confidence intervals (CIs) was calculated.ResultsFourteen studies and 46 983 participants were included in this study. The pooled results illustrated that clopidogrel, prasugrel and ticagrelor were effective on prevention of ST. Patients treated with prasugrel (OR = 0.30, 95% CI = 0.052 ~ 0.73, P < 0.05) and ticagrelor (OR = 0.25, 95% CI = 0.035 ~ 0.65, P < 0.05) had lower incidence of ST compared to those treated with clopidogrel. Patients treated with ticagrelor showed similar frequency with those in prasugrel group (OR = 0.86, 95% CI = 0.22 ~ 2.3, P > 0.05). No significant heterogeneity was observed across included studies.ConclusionsOur findings suggest that prasugrel and ticagrelor are more effective than clopidogrel on prevention of ST among patients underwent PCI. Simultaneously, there is no significant difference in the prevention of ST between prasugrel and ticagrelor.

The Effect of Platelet-Rich Plasma on Endothelial Progenitor Cell Functionality.

Platelets mediate circulating endothelial progenitor cell (EPC) recruitment and maturation, participating in vascular repair, however the underlying mechanism(s) remain unclear. We investigated the effect of platelet-rich plasma (PRP) on the functionality of CD34+-derived late-outgrowth endothelial cells (OECs) in culture. Confluent OECs were coincubated with PRP under platelet aggregation (with adenosine diphosphate; ADP) and nonaggregation conditions, in the presence/absence of the reversible P2Y12 platelet receptor antagonist ticagrelor. Outgrowth endothelial cell activation was evaluated by determining prostacyclin (PGI2) and monocyte chemoattractant protein-1 (MCP-1) release and intercellular adhesion molecule-1 (ICAM-1) membrane expression. Similar experiments were performed using human umbilical vein endothelial cells (HUVECs). Platelet-rich plasma increased ICAM-1 expression and PGI2 and MCP-1 secretion compared with autologous platelet-poor plasma, whereas ADP-aggregated platelets in PRP did not exhibit any effect. Platelet-rich plasma pretreated with ticagrelor prior to activation with ADP increased all markers to a similar extent as PRP. Similar results were obtained using HUVECs. In conclusion, PRP induces OEC activation, a phenomenon not observed when platelets are aggregated with ADP. Platelet inhibition with ticagrelor restores the PRP capability to activate OECs. Since EPC activation is important for endothelial regeneration and angiogenesis, we suggest that agents inhibiting platelet aggregation, such as ticagrelor, may promote platelet-EPC interaction and EPC function.

Use of the VerifyNow point of care assay to assess the pharmacodynamic effects of loading and maintenance dose regimens of prasugrel and ticagrelor

Prasugrel and ticagrelor are potent oral platelet P2Y12 inhibitors and are recommended over clopidogrel in patients with acute coronary syndrome (ACS). Oral platelet P2Y12 inhibitors are characterized by varying degrees of pharmacodynamic response profiles as assessed by a variety of commercially available assays. Because of its ease of use, rapid turnaround times and ability to provide results specific to P2Y12 inhibitory effects, VerifyNow has emerged as one of the most commonly utilized platelet function assays. However, reference ranges with VerifyNow have been reported mainly for clopidogrel and there has not yet been any study specifically conducted to provide the expected on treatment reference ranges following administration of prasugrel and ticagrelor. This was a prospective single center investigation conducted in 120 patients with ACS who were treated with prasugrel or ticagrelor as per standard of care. Patients who underwent percutaneous coronary interventions (PCI) were treated with a loading dose of prasugrel (60 mg) or ticagrelor (180 mg), and patients who were on maintenance therapy were taking prasugrel (10 mg qd or 5 mg qd) or ticagrelor (90 mg bid). Platelet function testing was performed using the VerifyNow™ PRUTest™. The overall range of PRUTest values was lower than that observed in studies of patients treated with clopidogrel. The use of a maintenance dose regimen had a wider range of PRUTest values compared to the use of a loading dose for both prasugrel (1–179 vs. 2–128) and ticagrelor (1–196 vs. 1–177). The average PRUTest values in patients on prasugrel and ticagrelor maintenance dosing were 20% and 9% higher those observed in patients treated with a loading dose. PRUTest results following loading dose administration were very similar between drugs, but were 20% higher with prasugrel compared with ticagrelor during maintenance dosing. This study establishes expected PRUTest ranges for patients taking loading and maintenance doses of prasugrel and ticagrelor.Clinical Trial Registrationhttp://www.clinicaltrials.gov Unique Identifier: NCT04492423, registered July 2020 retrospectively registered.

Impact of periprocedural morphine use on mortality in STEMI patients treated with primary PCI.

Intravenous morphine (MO) decreases the effect of all oral platelet P2Y12 receptor inhibitors in vitro and observational reports suggest that its use may be associated with larger infarct size. Yet, there are limited data available about the impact of this interaction on clinical outcomes. We studied the effect of MO on mortality in ST-segment elevation myocardial infarction (STEMI) patients treated with primary PCI using a prospective registry. Of the 1255 patients who underwent primary PCI, 397 received MO based on physician's judgment. Clopidogrel was used as P2Y12 receptor antagonist in all cases. Median follow-up time was 7.5 years with 457 deaths. To adjust for confounding, two propensity score-based procedures were performed: 1 to 1 matching (PSM, 728 cases), and inverse probability of treatment weighting (IPTW) retaining data from all patients. Primary outcome measure was time to all-cause death, whereas predischarge left ventricular ejection fraction (LVEF) was used as secondary end point. An adequate balance on baseline covariates was achieved by both methods. We found no difference in survival as the HR (MO/no MO) was 0.98 (95% confidence interval [CI]: 0.76-1.26), p = 0.86 using PSM and 1.01 (95% CI: 0.84-1.23), p = 0.88 with IPTW. Likewise, distributions of LVEFs were similar using either methods: with PSM, median LVEFs were 50.0% (interquartile range [IQR]: 43.0%-55.3%) vs 50.0% (IQR: 42.0%-55.0%) in the no MO and MO groups, respectively (p = 0.76), whereas using IPTW, they were 50.0% (IQR: 42.5%-55.0%) vs 50.0% (IQR: 41.0%-55.0%), respectively (p = 0.86). Our data suggest that morphine use may have no impact on long-term mortality and on predischarge ejection fraction in STEMI patients treated with primary PCI.

Ticagrelor: clinical development and future potential.

Platelets participate centrally in atherothrombosis, resulting in vessel occlusion and ischaemia. Consequently, optimisation of antiplatelet regimens has the potential to further reduce the residual burden of morbidity and mortality associated with atherosclerosis. Ticagrelor is a potent oral platelet P2Y12 receptor antagonist that (1) inhibits a central amplification pathway of platelet activation directly as well as via an active metabolite, (2) has a rapid onset and offset of antiplatelet action that remains consistent in the circulation during twice-daily administration and is amenable to reversal, (3) has inverse agonist properties, and (4) demonstrates pleiotropic effects that contribute to anti-thrombotic, anti-inflammatory and vasodilatory properties. These advantageous characteristics of ticagrelor have translated to beneficial clinical outcomes in patients with acute coronary syndromes or ischaemic stroke, during prolonged maintenance therapy in specific high-risk populations, and following percutaneous coronary intervention but not definitively following coronary artery bypass graft surgery or in peripheral artery disease patients. Novel innovative strategies aim to reduce the risk of bleeding during dual antiplatelet therapy via shortening the duration of treatment and replacing the standard-of-care with ticagrelor monotherapy. In cases where aspirin is an essential component in secondary prevention, dose modification when combined with ticagrelor may hypothetically provide desirable clinical outcomes following appropriate clinical assessment as predicted by pharmacological studies. Overall, the future management of acute coronary syndromes could potentially involve the dichotomisation of antithrombotic therapies, whereby only those with high-risk of ischaemia, without a high-risk of bleeding, receive ticagrelor plus very-low-dose aspirin, while ticagrelor monotherapy is administered to the remaining majority.

Modern Antiplatelet Therapy for Percutaneous Coronary Intervention. How to Make the Right Choice?

Dual antiplatelet therapy is the most important step in acute coronary syndrome (ACS) treatment. The new generation of inhibitors of P2Y12 platelet receptors (prasugrel and ticagrelor) provide more pronounced platelet inhibition than clopidogrel. The drugs differ in pharmacodynamics and platelet reactivity tests due to different mechanisms of binding to P2Y12 receptors. The antiplatelet effect of prasugrel and ticagrelor provides clinical benefit and better prognosis in patients with various forms of ACS. In patients with ST-segment elevation ACS prasugrel and ticagrelor are preferred over clopi-dogrel due to their higher efficacy and better clinical outcomes, and currently have preferential positions in guidelines compared to clopidogrel. The comparison of prasugrel versus ticagrelor (ISAR-REACT 5 trial) demonstrated superiority of prasugrel over ticagrelor in patients with ST-segment elevation ACS, for whom an invasive evaluation is planned and in early invasive treatment non-ST-segment elevation ACS. The choice of a drug for dual antiplatelet therapy in various clinical situations remains controversial. The latest ESC guidelines on non-ST elevation ACS (2020) [1] demonstrate the possible preference for prasugrel in patients with ACS without ST-segment elevation undergoing percutaneous coronary intervention. Current article demonstrates the results of recent clinical studies and the real clinical data regarding antiplatelet therapy in patients with coronary interventions. The indications for the use of P2Y12 platelet inhibitors in certain groups of patients are outlined. Treatment selection of the most effective and safe drugs in patients with ACS is highlighted according to the updated European guidelines.

Implications of the Antiplatelet Therapy Gap Left With Discontinuation of Prasugrel in Canada

BackgroundThe current Canadian Cardiovascular Society antiplatelet therapy guidelines recommend the use of ticagrelor or prasugrel over clopidogrel as first-line platelet P2Y12 receptor antagonists for treatment of moderate- to high-risk acute coronary syndromes. Recently, Effient (prasugrel [Eli Lilly Canada Inc, Toronto, Canada]) was discontinued by its distributor in Canada. MethodsFive members of the Canadian Cardiovascular Society antiplatelet therapy 2018 guidelines committee undertook an independent, evidence-based review to outline patients for whom prasugrel should be the optimal P2Y12 agent and discuss alternative strategies to consider without prasugrel. ResultsSeveral clinical scenarios where prasugrel should be indicated are identified and discussed. Considerations to be undertaken for alternative therapies are summarized, including a review of national and international guidelines for de-escalation of P2Y12 receptor antagonists. ConclusionsThe discontinuation of prasugrel poses a challenge for clinicians. Clinicians must consider key factors in determining the best alternate therapy.

Regarding the choice of Р2У&lt;sub&gt;12&lt;/sub&gt; platelet receptor blocker in the early invasive approach to acute coronary syndrome treatment in patients without indications for long-term anticoagulant use

In case of early invasive approach to the treatment of acute coronary syndrome in patients without indications forlong-term anticoagulants, double antithrombocytic therapy is recommended - a combination of acetylsalicylic acid with one of the blockers of P2Y12 platelet receptor (clopidogrel, prasugrel or ticagrelor). In this case, patients who do not have an excessively high risk of bleeding, there is evidence in favor of the choice of prasugrel or ticagrelor. Which of them is preferable in cases where in the first hours after hospitalization it is planned to perform coronary stenting is not fully clarified.The drawbacks of the randomized open PRAGUE-18 study do not allow us to judge the comparative effectiveness and safety of prasugrel and ticagrelor in primary percutaneous coronary intervention.ц The ISAR-REACT 5 study was relatively small and has its strengths as well as weaknesses. However, the European expert community considers the results to be sufficient to change the practical approaches to acute coronary syndrome treatment. Thus, according to the recommendations of the European Society of Cardiology for the treatment of acute coronary syndrome without stable ST segment elevations on ECG, which were updated in September 2020, prasugrel is proposed to be considered as a preferred treatment for ticagrelor in cases where the patient is directed to percutaneous coronary intervention (class IIa recommendation, degree of evidence B).

Ticagrelor Plus Aspirin for Stroke or TIA of Atherosclerotic Origin

Ticagrelor is a reversible platelet P2Y12 receptor inhibitor. The recently completed THALES trial, comparing aspirin plus ticagrelor (A+T) versus

ADP-Mediated Upregulation of Expression of CD62P on Human Platelets Is Critically Dependent on Co-Activation of P2Y1 and P2Y12 Receptors.

This study probed the differential utilization of P2Y1 and P2Y12 receptors in mobilizing CD62P (P-selectin) from intracellular granules following activation of human platelets with adenosine 5′-diphosphate (ADP, 100 µmol·L−1) Platelet-rich plasma (PRP) was prepared from the blood of adult humans. CD62P was measured by flow cytometry following activation of PRP with ADP in the absence and presence of the selective antagonists of P2Y1 and P2Y12 receptors, MRS2500 and PSB0739 (both 0.155–10 µmol·L−1), respectively. Effects of the test agents on ADP-activated, CD62P-dependent formation of neutrophil:platelet (NP) aggregates were also measured by flow cytometry, while phosphatidylinositol 3-kinase (PI3K) activity was measured according to Akt1 phosphorylation in platelet lysates. Treatment with MRS2500 or PSB0739 at 10 µmol·L−1 almost completely attenuated (94.6% and 86% inhibition, respectively) ADP-activated expression of CD62P and also inhibited NP aggregate formation. To probe the mechanisms involved in P2Y1/P2Y12 receptor-mediated expression of CD62P, PRP was pre-treated with U73122 (phospholipase C (PLC) inhibitor), 2-aminoethoxy-diphenyl borate (2-APB, inositol triphosphate receptor antagonist), calmidazolium chloride (calmodulin inhibitor), or wortmannin (PI3K inhibitor). U73122, 2-APB, and wortmannin caused almost complete inhibition of ADP-activated expression of CD62P, while calmidazolium chloride caused statistically significant, partial inhibition. PSB0739, but not MRS2500, caused potent inhibition of PI3K-mediated phosphorylation of Akt1. Optimal mobilization of CD62P by ADP-stimulated platelets is critically dependent on the co-activation of platelet P2Y1 and P2Y12 receptors. P2Y12 receptor activation is the key event in activation of PI3K, while activation of the P2Y1 receptor appears to create a high cytosolic Ca2+ environment conducive to optimum PI3K activity.

Effects of morphine on P2Y12 platelet inhibitors in patients with acute myocardial infarction: A meta-analysis.

To explore the effects of morphine on P2Y12 platelet inhibitors in patients with acute myocardial infarction (AMI). PubMed, Embase, Cochrane Library, and Web of Science were used to retrieve literature through 11th May 2019. Standardized weighted mean difference (SMD) and relative risk (RR) with 95% confidence intervals (CI), P-value, and I2 value were used to assess the strength of the association in this meta-analysis. Outcomes included platelet reactivity, high residual platelet reactivity (HRPR), ticagrelor maximum concentration (Cmax), ticagrelor area under curve (AUC), death rate, reinfarction rate, stroke, stent thrombosis, thrombolysis in myocardial infarction (TIMI) hemorrhage, dyspnea, emesis, contrast-induced nephropathy, and pulmonary edema. A total of 13 articles were included in this study, containing 5688 patients (morphine group: n=2014, control group: n=3674). Results illustrated that the morphine group had a higher platelet reactivity (SMD: 0.834, 95%CI: 0.483-1.186, P<0.001) and HRPR rate (RR: 1.994, 95%CI: 1.536-2.588, P<0.001) than the control group, while the Cmax of ticagrelor (WMD: -481.838, 95%CI: -841.242-122.434, P=0.009) was lower than that of the control group. The death rate of the morphine group was lower than that in the control group (RR: 0.561, 95%CI: 0.337-0.933, P=0.026). The morphine group had a higher emesis rate than the control group (RR: 4.486, 95%CI: 2.263-8.891, P<0.001). Morphine effectively suppresses the inhibition effect of P2Y12 platelet inhibitors in patients with AMI.

Epigenetic interaction of miRNA-26a and P2Y12 gene DNA methylation on platelet reactivity under clopidogrel and their impact to the coronary flow after primary PCI in STEMI

Abstract Background Epigenetic factors such as miRNA-26A and P2Y12 DNA methylation play role in pathophysiology of cardiovascular disease. Clopidogrel-resistance is associated with worse cardiovascular outcome. The interactions between the expression of platelet miRNA-26a and P2Y12 DNA methylation to clopidogrel resistance and post procedural TIMI flow in STEMI patients undergoing primary PCI is unclear. Purpose To define interaction of epigenetic factors micro-RNA (miRNA)-26a expression and P2Y12 gene DNA methylation to the platelet reactivity under clopidogrel therapy, and their impact on the coronary flow after Primary PCI in patients with STEMI. Methods We studied STEMI patients who underwent primary PCI, receiving 600 mg loading dose of clopidogrel. Platelet reactivity assessed by VerifyNow P2Y12. Realtime PCR was performed to measure the expression of platelet miR-26a and DNA methylation of P2Y12 gene. Postprocedural epicardial coronary flow was assessed semi quantitatively. Results There were 100 patients were recruited. Among them, 59% have high miRNA-26a platelet expression, 60% had no methylation in their P2Y12 gene, and 27% had high platelet reactivity index under clopidogrel therapy. There was association between high miR-26a expression and reduced platelet inhibition under clopidogrel (OR 4.2, p&amp;lt;0.01), but not with DNA methylation of P2Y12 gene. High platelet reactivity index under clopidogrel therapy was associated with suboptimal coronary flow after primary PCI in STEMI patients (OR 3.3, p&amp;lt;0.05). Conclusions High miRNA-26a platelet expression, but not DNA methylation of P2Y12 gene, in patients with acute STEMI have significant association with high platelet reactivity under clopidogrel therapy. Furthermore, high platelet reactivity under clopidogrel is associated with suboptimal coronary flow in STEMI patients undergoing primary PCI. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Harapan Kita Honor Research Grant

Lumbar puncture in patients on anticoagulants

Lumbar puncture is an important invasive procedure often used in the diagnosis of neurological disorders. Generally, lumbar puncture is a safe procedure, with a very low incidence of serious complications, the risk of which, however, may increase in the group of patients on anticoagulant therapy (anticoagulants and platelet anti-aggregation agents). This applies to both the risk of haemorrhagic complications and the risk of thrombotic events during temporary discontinuation of anticoagulants. This paper presents the current knowledge on the management in patients receiving anticoagulants (vitamin K antagonists, new anticoagulants, heparins, fondaparinux) and platelet anti-aggregation agents (P2Y12 platelet receptor antagonists, glycoprotein IIb/IIIa inhibitors, acetylsalicylic acid) who require lumbar puncture. Furthermore, we present the issue of bridging therapy in patients at a high risk of thrombotic complications. In the case of neurological indications for a lumbar puncture in a patient on anticoagulants or anti-aggregation therapy, the urgency of the procedure and the risk of adverse effects should be assessed and other diagnostic methods should be considered in the first place. If there is a need for an urgent lumbar puncture, treatment modification or the use of drugs to reverse the anticoagulant or anti-aggregation effect may be necessary. Each case must be treated individually, considering medical and family history, comorbidities and other medications taken by the patient. Most of the available recommendations related to the presented problem have been developed by anaesthetic associations. There is a need to popularise the principles of management in patients on anticoagulants who require lumbar puncture due to neurological disorders.

Association of Ticagrelor vs Clopidogrel With Net Adverse Clinical Events in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

Current guidelines recommend ticagrelor as the preferred P2Y12 platelet inhibitor for patients with acute coronary syndrome (ACS), primarily based on a single large randomized clinical trial. The benefits and risks associated with ticagrelor vs clopidogrel in routine practice merits attention. To determine the association of ticagrelor vs clopidogrel with ischemic and hemorrhagic events in patients undergoing percutaneous coronary intervention (PCI) for ACS in clinical practice. A retrospective cohort study of patients with ACS who underwent PCI and received ticagrelor or clopidogrel was conducted using 2 United States electronic health record-based databases and 1 nationwide South Korean database from November 2011 to March 2019. Patients were matched using a large-scale propensity score algorithm, and the date of final follow-up was March 2019. Ticagrelor vs clopidogrel. The primary end point was net adverse clinical events (NACE) at 12 months, composed of ischemic events (recurrent myocardial infarction, revascularization, or ischemic stroke) and hemorrhagic events (hemorrhagic stroke or gastrointestinal bleeding). Secondary outcomes included NACE or mortality, all-cause mortality, ischemic events, hemorrhagic events, individual components of the primary outcome, and dyspnea at 12 months. The database-level hazard ratios (HRs) were pooled to calculate summary HRs by random-effects meta-analysis. After propensity score matching among 31 290 propensity-matched pairs (median age group, 60-64 years; 29.3% women), 95.5% of patients took aspirin together with ticagrelor or clopidogrel. The 1-year risk of NACE was not significantly different between ticagrelor and clopidogrel (15.1% [3484/23 116 person-years] vs 14.6% [3290/22 587 person-years]; summary HR, 1.05 [95% CI, 1.00-1.10]; P = .06). There was also no significant difference in the risk of all-cause mortality (2.0% for ticagrelor vs 2.1% for clopidogrel; summary HR, 0.97 [95% CI, 0.81-1.16]; P = .74) or ischemic events (13.5% for ticagrelor vs 13.4% for clopidogrel; summary HR, 1.03 [95% CI, 0.98-1.08]; P = .32). The risks of hemorrhagic events (2.1% for ticagrelor vs 1.6% for clopidogrel; summary HR, 1.35 [95% CI, 1.13-1.61]; P = .001) and dyspnea (27.3% for ticagrelor vs 22.6% for clopidogrel; summary HR, 1.21 [95% CI, 1.17-1.26]; P < .001) were significantly higher in the ticagrelor group. Among patients with ACS who underwent PCI in routine clinical practice, ticagrelor, compared with clopidogrel, was not associated with significant difference in the risk of NACE at 12 months. Because the possibility of unmeasured confounders cannot be excluded, further research is needed to determine whether ticagrelor is more effective than clopidogrel in this setting.

High glycated albumin is an independent predictor of low response to clopidogrel in ACS patients: a cross-sectional study

BackgroundGlycated albumin (GA) is a marker of short-term glycemic control and is strongly associated with the occurrence of diabetes. Previous studies have shown an association between GA and the effect of clopidogrel therapy on ischemic stroke. However, limited information is available regarding this relationship in acute coronary syndrome (ACS) patients. In this study, we evaluated the effect of GA on platelet P2Y12 inhibition by clopidogrel in patients with ACS.MethodsConsecutive Chinese patients with ACS who received loading or maintenance doses of clopidogrel in addition to aspirin were recruited. At least 12 h after the patient had taken the clopidogrel dose, thromboelastography (TEG) and light transmittance aggregometry (LTA) were used to calculate the quantitative platelet inhibition rate to determine clopidogrel-induced antiplatelet reactivity. A prespecified cutoff of the maximum amplitude of adenosine diphosphate (ADP)-induced platelet-fibrin clot strength > 47 mm plus an ADP-induced platelet inhibition rate < 50% assessed by TEG or ADP-induced platelet aggregation > 40% assessed by LTA to indicate low responsiveness to clopidogrel were applied for evaluation. Patients were categorized into two groups based on a GA level of 15.5%, the cutoff point indicating the development of early-phase diabetes. Multivariate linear regression analysis was used to assess the interaction of GA with clopidogrel antiplatelet therapy.ResultsA total of 1021 participants were evaluated, and 28.3% of patients (289 of 1021) had low responsiveness to clopidogrel assessed by TEG. In patients with elevated GA levels, low responsiveness to clopidogrel assessed by TEG was observed in 33.7% (139 of 412) of patients, which was a significantly higher rate than that in the lower-GA-level group (24.6%, P = 0.002). According to multivariate linear regression analysis, a GA level > 15.5% was independently associated with low responsiveness to clopidogrel after adjustment for age, sex and other conventional confounding factors. This interaction was not mediated by a history of diabetes mellitus. A GA level ≤ 15.5% was associated with a high positive value [75.4%, 95% CI 73.0–77.6%] for predicting a normal responsiveness to clopidogrel.ConclusionsGA could be a potential biomarker to predict the effects of clopidogrel antiplatelet therapy in ACS patients and might be a clinical biomarker to guide DAPT de-escalation.

A geranylated chalcone with antiplatelet activity from the leaves of breadfruit (Artocarpus altilis)

Platelet plays a crucial role in cardiovascular diseases (CVDs) development. Abnormalities in platelet aggregation provokes thromboembolism, eventually leading to death. In Indonesia, breadfruit (Artocarpus altilis) leaf is traditionally used to treat CVDs. This study aimed to evaluate the antiplatelet activity of A. altilis leaf extract (AAE) and to identify its active compound. A. altilis leaves were extracted with ethanol, and the antiplatelet activity was assessed using ADP-induced platelet aggregation. The major compound was isolated with column chromatography followed by preparative TLC, and the structure was determined on the basis of UV, MS, IR, and NMR spectra. The binding mode of the active compound to platelet receptors was characterized in in silico study. AAE exhibited an antiplatelet activity (IC50 of 252.23 µg/mL). A geranylated chalcone, 2-geranyl-2ʹ,3,3,4ʹ-tetrahydroxydihydrochalcone (GTDC) was identified as the antiplatelet compound (IC50 of 9.09 µM). GTDC actions with P2Y12 platelet receptor involving three amino acid residues.

Comparison of platelet reactivity between prasugrel and ticagrelor in patients with acute coronary syndrome: a meta-analysis

BackgroundThis meta-analysis aimed to compare the effects of prasugrel and ticagrelor on high (HTPR) and low on-treatment platelet reactivity (LTPR) in patients with acute coronary syndrome (ACS).MethodsEligible studies were retrieved from PubMed, Embase, and the Cochrane Library. HTPR and LTPR were evaluated on the basis of the vasodilator-stimulated phosphoprotein platelet reactivity index (VASP-PRI) and P2Y12 reaction units (PRUs). HTPR and LTPR were analyzed using risk ratios (RRs) and their 95% confidence intervals (CIs). Weighted mean difference (WMD) and 95% CI were used to calculate the pooled effect size of platelet reactivity (PR).ResultsFourteen eligible studies were obtained, which included 2629 patients treated with ticagrelor (n = 1340) and prasugrel (n = 1289). The pooled results showed that the prasugrel-treated patients had higher platelet reactivity than the ticagrelor-treated patients (PRU: WMD = − 32.26; 95% CI: − 56.48 to − 8.76; P < 0.01; VASP-PRI: WMD = − 9.61; 95% CI: − 14.63 to − 4.60; P = 0.002). No significant difference in HTPR based on PRU was identified between the ticagrelor and prasugrel groups (P = 0.71), whereas a lower HTPR based on VASP-PRI was found in the ticagrelor-treated patients than in the prasugrel-treated patients (RR = 0.30; 95% CI: 0.12–0.75; P = 0.010). In addition, the results showed a lower LTPR was observed in the prasugrel group than in the ticagrelor group (RR = 1.40; 95% CI: 1.08–1.81; P = 0.01).ConclusionsPrasugrel might enable higher platelet reactivity than ticagrelor. Ticagrelor could lead to a decrease in HTPR and increase in LTPR. However, this result was only obtained in pooled observational studies. Several uncertainties such as the nondeterminancy of the effectiveness of ticagrelor estimated using VASP-PRI or the definition of HTPR (a high or modifiable risk factor) might have affected our results.

From the antiplatelet drug ticagrelor to antibiotics: A study of structure-activity relationships

Ticagrelor is an orally active antiplatelet drug belonging to 1,2,3-triazolo[4,5-d]pyrimidines, which acts by reversibly inhibiting the platelet P2Y12 receptor for ADP. Although ticagrelor does not need to be metabolized to be active in vivo, it is extensively metabolized to form a main metabolite known as AR-C124910, equally potent to inhibit P2Y12 receptors. Importantly, we recently discovered that ticagrelor and AR-C124910 exert bactericidal and anti-biofilm activity against gram-positive bacteria. The present work aimed at establishing structure-activity relationships of a series of 1,2,3-triazolo[4,5-d]pyrimidines in order to identify structural determinants of antiplatelet and antibacterial activity. Ticagrelor, five main metabolites and eighteen 1,2,3-triazolo[4,5-d]pyrimidines lacking different chemical groups or bearing atom substitutions were synthetized. The antiplatelet activity of the test molecules was analysed by light transmission aggregometry upon platelet stimulation with ADP in citrated platelet-rich-plasma. The antibacterial activity against Staphylococcus aureus strains was determined by the broth microdilution method. Only ticagrelor and AR-C124910 showed antibacterial activity. We found out that molecules lacking either the difluorphenylcyclopropyl group or the hydroxyethoxy cyclopentane-1,2-diol were all inactive against bacteria. Interestingly, such restriction did not apply to the antiplatelet activity. Indeed, seven of these molecules, devoid of antibacterial activity, still inhibited the ADP-induced platelet aggregation. We identified molecules that preserved potent antiplatelet activity while being inactive against S. aureus . These molecules might help demonstrating ticagrelor antibacterial activity in vivo, independently of or in addition to its antiplatelet activity.

Effect of CYP3A4*22 and PPAR-α Genetic Variants on Platelet Reactivity in Patients Treated with Clopidogrel and Lipid-Lowering Drugs Undergoing Elective Percutaneous Coronary Intervention.

This study aims to determine whether genetic variants that influence CYP3A4 expression are associated with platelet reactivity in clopidogrel-treated patients undergoing elective percutaneous coronary intervention (PCI), and to evaluate the influence of statin/fibrate co-medication on these associations. A study cohort was used containing 1124 consecutive elective PCI patients in whom CYP3A4*22 and PPAR-α (G209A and A208G) SNPs were genotyped and the VerifyNow P2Y12 platelet reactivity test was performed. Minor allele frequencies were 0.4% for CYP3A4*22/*22, 6.8% for PPAR-α G209A AA, and 7.0% for PPAR-α A208G GG. CYP3A4*22 was not associated with platelet reactivity. The PPAR-α genetic variants were significantly associated with platelet reactivity (G209A AA: −24.6 PRU [−44.7, −4.6], p = 0.016; A208G GG: −24.6 PRU [−44.3, −4.8], p = 0.015). Validation of these PPAR-α results in two external cohorts, containing 716 and 882 patients, respectively, showed the same direction of effect, although not statistically significant. Subsequently, meta-analysis of all three cohorts showed statistical significance of both variants in statin/fibrate users (p = 0.04 for PPAR-a G209A and p = 0.03 for A208G), with no difference in statin/fibrate non-users. In conclusion, PPAR-α G209A and A208G were associated with lower platelet reactivity in patients undergoing elective PCI who were treated with clopidogrel and statin/fibrate co-medication. Further research is necessary to confirm these findings.