Ticagrelor increases its own potency at the P2Y12 receptor by directly changing the plasma membrane lipid order in platelets.

BACKGROUND AND PURPOSE: Although the amphiphilic nature of the widely used antithrombotic drug Ticagrelor is well known, it was never considered as a membranotropic agent capable of interacting with the lipid bilayer in a receptor-independent way. In this study, we investigated the influence of Ticagrelor on plasma membrane lipid order in platelets and if this modulates the potency of Ticagrelor at the P2Y12 receptor. EXPERIMENTAL APPROACH: We combined fluorescent in situ, in vitro and in silico approaches to probe the interactions between the plasma membrane of platelets and Ticagrelor. The influence of Ticagrelor on the lipid order of the platelet plasma membrane and large unilamellar vesicles was studied using the advanced fluorescent probe NR12S. Furthermore, the properties of model lipid bilayers in the presence of Ticagrelor were characterized by molecular dynamics simulations. Finally, the influence of an increased lipid order on the dose-response of platelets to Ticagrelor was studied. KEY RESULTS: Ticagrelor incorporates spontaneously into lipid bilayers and affects the lipid order of the membranes of model vesicles and isolated platelets, in a nontrivial composition and concentration-dependent manner. We showed that higher plasma membrane lipid order in platelets leads to a lower IC50 value for Ticagrelor. It is shown that membrane incorporation of Ticagrelor increases its potency at the P2Y12 receptor, by increasing the order of the platelet plasma membrane. CONCLUSION AND IMPLICATIONS: A novel dual mechanism of Ticagrelor action is suggested that combines direct binding to P2Y12 receptor with simultaneous modulation of receptor-lipid microenvironment.

P2Y12 Inhibition in Patients Requiring Oral Anticoagulation After Percutaneous Coronary Intervention: The SWAP-AC-2 Study.

BACKGROUND: Among patients treated with a novel oral anticoagulant (NOAC) undergoing percutaneous coronary intervention (PCI), combination therapy with clopidogrel (ie, known as dual antithrombotic therapy [DAT]) is the treatment of choice. However, there are concerns for individuals with impaired response to clopidogrel. OBJECTIVES: The authors sought to assess the pharmacodynamic (PD) effects of clopidogrel vs low-dose ticagrelor in patients with impaired clopidogrel response assessed by the ABCD-GENE score. METHODS: This was a prospective, randomized PD study of NOAC-treated patients undergoing PCI. Patients with an ABCD-GENE score ≥10 (n = 39), defined as having impaired clopidogrel response, were randomized to low-dose ticagrelor (n = 20; 60 mg twice a day) or clopidogrel (n = 19; 75 mg once a day). Patients with an ABCD-GENE score <10 (n = 42) were treated with clopidogrel (75 mg once a day; control cohort). PD assessments at baseline and 30 days post-randomization (trough and peak) were performed to assess P2Y12 signaling (VerifyNow P2Y12 reaction units [PRU], light transmittance aggregometry, and vasodilator-stimulated phosphoprotein); makers of thrombosis not specific to P2Y12 signaling were also assessed. The primary endpoint was PRU (trough levels) at 30 days. RESULTS: At 30 days, PRU levels were reduced with ticagrelor-based DAT compared with clopidogrel-based DAT at trough (23.0 [Q1-Q3: 3.0-46.0] vs 154.5 [Q1-Q3: 77.5-183.0]; P < 0.001) and peak (6.0 [Q1-Q3: 4.0-14.0] vs 129.0 [Q1-Q3: 66.0-171.0]; P < 0.001). Trough PRU levels in the control arm (104.0 [Q1-Q3: 35.0-167.0]) were higher than ticagrelor-based DAT (P = 0.005) and numerically lower than clopidogrel-based DAT (P = 0.234). Results were consistent by light transmittance aggregometry and vasodilator-stimulated phosphoprotein. Markers measuring other pathways leading to thrombus formation were largely unaffected. CONCLUSIONS: In NOAC-treated patients undergoing PCI with an ABCD-GENE score ≥10, ticagrelor-based DAT using a 60-mg, twice-a-day regimen reduced platelet P2Y12 reactivity compared with clopidogrel-based DAT. (Tailoring P2Y12 Inhibiting Therapy in Patients Requiring Oral Anticoagulation After PCI [SWAP-AC-2]; NCT04483583).

Antithrombotic Stewardship: Evaluation of Platelet Reactivity-Guided Cangrelor Dosing Using the VerifyNow Assay.

ABSTRACT: Cangrelor may be used as a bridge when temporary interruption of dual antiplatelet therapy is necessary. However, the optimal dose and monitoring of cangrelor in patients remains unknown, especially in the setting of mechanical circulatory support (MCS). We conducted an observational, single-center, retrospective cohort study of patients who had percutaneous coronary intervention within 3 months and received cangrelor while admitted to any intensive care unit. The primary outcome was the incidence of any major adverse cardiovascular event. Secondary outcomes included VerifyNow platelet reactivity units (PRUs) measured while on cangrelor and any bleeding events while on cangrelor. A total of 92 patients were included. The most common reason for cangrelor use was in the periprocedural setting, with or without MCS (42%-45%), followed by NPO status (26%-28%) and MCS alone (22%-24%). The primary outcome of major adverse cardiovascular event occurred in 1 patient (1.1%). Of 92 patients, 77% had a P2Y12 level collected within 24 hours, and 89% of the cohort was able to achieve the goal P2Y12 PRU of <194. The median P2Y12 value within 24 hours of cangrelor initation was 115 PRU (40-168 PRU). We observed a bleed event rate of 23% (21/92). We found a standardized protocol of cangrelor dosing in critically ill patients who received a drug-eluting stent in the past 3 months to be successful in achieving a goal P2Y12 PRU. Although the optimal PRU remains unknown, cardiovascular clinicians may monitor these levels to help guide decisions regarding cangrelor management. Future randomized controlled trials should evaluate the optimal PRU threshold to balance risks of ischemia and bleeding.

Assessment of Pretreatment With Oral P2Y12 Inhibitors and Cardiovascular and Bleeding Outcomes in Patients With Non-ST Elevation Acute Coronary Syndromes: A Systematic Review and Meta-analysis.

Importance: The practice of pretreatment with oral P2Y12 inhibitors in non-ST elevation acute coronary syndromes (NSTEACS) remains common; however, its association with improved cardiovascular outcomes is unclear. Objective: To assess the association between oral P2Y12 inhibitor pretreatment and cardiovascular and bleeding outcomes in patients with NSTEACS. Data Sources: On March 20, 2021, PubMed, MEDLINE, Embase, Scopus, Web of Science, Science Direct, clinicaltrials.gov, and the Cochrane Central Register for Controlled Trials were searched from database inception. Study Selection: Randomized clinical trials of patients with NSTEACS randomized to either oral P2Y12 inhibitor pretreatment (defined as prior to angiography) or no pretreatment (defined as following angiography, once coronary anatomy was known) among patients undergoing an invasive strategy. Data Extraction and Synthesis: This study followed Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data on publication year, sample size, clinical characteristics, revascularization strategy, P2Y12 inhibitor type and dosage, time from pretreatment to angiography, and end point data were independently extracted by 2 authors. A random-effects model was used, including stratification by (1) P2Y12 inhibitor type, (2) revascularization strategy, and (3) access site. Main Outcomes and Measures: The primary end point was 30-day major adverse cardiac events (MACEs). Secondary end points were 30-day myocardial infarction (MI) and cardiovascular death. The primary safety end point was 30-day major bleeding (defined according to individual studies). Results: A total of 7 trials randomizing 13 226 patients to either pretreatment (6603 patients) or no pretreatment (6623 patients) were included. The mean age of patients was 64 years and 3598 (27.2%) were female individuals. Indication for P2Y12 inhibitors was non-ST elevation myocardial infarction in 7430 patients (61.7%), radial access was used in 4295 (32.6%), and 10 945 (82.8%) underwent percutaneous coronary intervention. Pretreatment was not associated with a reduction in 30-day MACE (odds ratio [OR], 0.95; 95% CI, 0.78-1.15; I2 = 28%), 30-day MI (OR, 0.90; 95% CI, 0.72-1.12; I2 = 19%), or 30-day cardiovascular death (OR, 0.79; 95% CI, 0.49-1.27; I2 = 0%). The risk of 30-day major bleeding was increased among patients who underwent pretreatment (OR, 1.51; 95% CI, 1.16-1.97; I2 = 41%). The number needed to harm to bring about 1 major bleeding event with oral P2Y12 inhibitor pretreatment was 63 patients. Conclusions and Relevance: In this study, pretreatment with oral P2Y12 inhibitors among patients with NSTEACS prior to angiography, compared with treatment once coronary anatomy is known, was associated with increased bleeding risk and no difference in cardiovascular outcomes. Routine pretreatment with oral P2Y12 inhibitors in patients with NSTEACS receiving an early invasive strategy is not supported by this study.

A2A receptor agonists and P2Y12 receptor antagonists modulate expression of thrombospondin-1 (TSP-1) and its secretion from Human Microvascular Endothelial Cells (HMEC-1).

BACKGROUNDS AND AIMS: To address the problem of resistance to standard antiplatelet therapy in some patients, our team proposed a purinoceptor-dependent dual therapy. Its efficacy is also determined by the condition of the vascular endothelium which, by secreting numerous factors, is involved in hemostasis. Among them, thrombospondin-1 is important in the context of thrombotic events. Therefore we sought to determine if the novel dual purinoceptor-dependent concept is associated with TSP-1 changes in vascular endothelial cells. METHODS AND RESULTS: TSP-1 expression in human microvascular endothelial cells was determined at transcriptional and protein level. We performed real-time PCR, the Western blot analysis and ELISA test. We found that TSP-1 mRNA and protein expression levels significantly changed in response to P1R agonists treatment. Furthermore, we have observed that co-administration of selective A2AR agonists (UK-432,097 or MRE0094) with P2Y12R antagonists altered TSP-1 expression levels, and the direction of these changes was not synergistic. MRE0094 applied with ARC69931MX or R-138727 increased mRNA expression from 39 to 56 or 57%, respectively (*P < 0.05 vs. MRE0094; ***P < 0.001 vs. control). Also, in the case of the P2Y12R antagonists used together with UK-432,097, there was an increase from 53 to 71 and 70% (*P < 0.05 vs. UK-432,097; ***P < 0.001 vs. control). The observed trends in gene expression were reflected in the protein expression and the level of its secretion from HMEC-1. CONCLUSION: The article presents evidence which proves that the purinoceptor-dependent concept is associated with TSP-1 changes in endothelial cells (EC). Moreover, Human Microvascular Endothelial Cells treatment applied together with agonists (MRE0094 or UK-432,097) and P2Y12R antagonist did not result in any synergistic effect, implicating a possible crosstalk between G proteins in GPCRs dependent signaling. Therefore, we suggest that understanding of the specific mechanism underlying TSP-1 alterations in EC in the context of the dual purinoceptor-dependent approach is essential for antiplatelet therapies and should be the subject of future research.

Translation of experimental cardioprotective capability of P2Y12 inhibitors into clinical outcome in patients with ST-elevation myocardial infarction.

We studied the translational cardioprotective potential of P2Y12 inhibitors against acute myocardial ischemia/reperfusion injury (IRI) in an animal model of acute myocardial infarction and in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). P2Y12 inhibitors may have pleiotropic effects to induce cardioprotection against acute myocardial IRI beyond their inhibitory effects on platelet aggregation. We compared the cardioprotective effects of clopidogrel, prasugrel, and ticagrelor on infarct size in an in vivo rat model of acute myocardial IRI, and investigated the effects of the P2Y12 inhibitors on enzymatic infarct size (48-h area-under-the-curve (AUC) troponin T release) and clinical outcomes in a retrospective study of STEMI patients from the CONDI-2/ERIC-PPCI trial using propensity score analyses. Loading with ticagrelor in rats reduced infarct size after acute myocardial IRI compared to controls (37 ± 11% vs 52 ± 8%, p < 0.01), whereas clopidogrel and prasugrel did not (50 ± 11%, p > 0.99 and 49 ± 9%, p > 0.99, respectively). Correspondingly, troponin release was reduced in STEMI patients treated with ticagrelor compared to clopidogrel (adjusted 48-h AUC ratio: 0.67, 95% CI 0.47-0.94). Compared to clopidogrel, the composite endpoint of cardiac death or hospitalization for heart failure within 12 months was reduced in STEMI patients loaded with ticagrelor (HR 0.63; 95% CI 0.42-0.94) but not prasugrel (HR 0.84, 95% CI 0.43-1.63), prior to PPCI. Major adverse cardiovascular events did not differ between clopidogrel, ticagrelor, or prasugrel. The cardioprotective effects of ticagrelor in reducing infarct size may contribute to the clinical benefit observed in STEMI patients undergoing PPCI.

Investigation of the interaction between proton pump inhibitors and clopidogrel using VerifyNow P2Y12 assay.

BACKGROUND: Randomized trials and observation studies have revealed conflicting results regarding the interaction between clopidogrel and proton pump inhibitors (PPIs). The aim of our study was to provide laboratory evidence regarding whether PPIs blunt the antiplatelet reactivity of clopidogrel. METHODS: We included records of Asian patients who received clopidogrel treatment for cardiovascular or cerebrovascular events and the VerifyNow P2Y12 assay for platelet reactivity monitoring. The responsiveness of antiplatelet effect to clopidogrel was analyzed according to 3 criteria:Results: Patients treated without PPIs did not differ significantly from those concomitantly treated with PPIs in terms of levels of PI (25.7% ± 24.3% vs 23.0 ± 25.3%, P = .4315), PRU (187.3 ± 74.0 vs 197.4 ±â€Š77.3, P = .3373), or responsiveness to antiplatelet (adjusted absolute risk, 3.5%; 95% confidence interval, - 10.7 to 17.7%; P = .6297). Patients treated with lansoprazole, esomeprazole, pantoprazole, and rabeprazole exhibited no significant differences in PRU or PI levels compared with those treated without PPIs. By contrast, patients treated with dexlansoprazole exhibited a significantly decreased level of PI (25.7% ±â€Š24.3% vs 14.0% ±â€Š21.6%, P = .0297) and responsiveness to clopidogrel under the criterion PI > 20% (adjusted absolute risk: 10.5%; 95% confidence interval: 2.6% to 43.6%; P = .0274). CONCLUSION: No robust interaction between clopidogrel and PPIs was found, but caution should be exercised in the concomitant use of dexlansoprazole and clopidogrel in Asians.

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

BACKGROUND: This 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). METHODS: Eligible 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). RESULTS: Fourteen 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). CONCLUSIONS: Prasugrel 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.

ATP and ADP enhance DNA damage repair in γ-irradiated BEAS-2B human bronchial epithelial cells through activation of P2X7 and P2Y12 receptors.

Agents that promote DNA repair may be useful as radioprotectants to minimize side effects such as radiation pneumonia caused by damage to normal cells during radiation therapy to treat lung cancer. We have reported that extracellular nucleotides and nucleosides are involved in the P2 or P1 receptor-mediated DNA damage response (DDR) after γ-irradiation. Here, we investigated the effects of ATP, UTP, GTP, ITP and their metabolites on the γH2AX/53BP1 focus formation in nuclei (a measure of γ-irradiation-induced DDR) and the survival of γ-irradiated immortalized human bronchial epithelial (BEAS-2B) cells. Fluorescence immunostaining showed that ATP and ADP increase DDR and DNA repair, and exhibit radioprotective effects as evaluated by colony formation assay. These effects of ATP or ADP were blocked by inhibitors of P2X7 or P2Y12 receptor, respectively, and by ERK1/2 inhibitor. ATP and ADP enhanced phosphorylation of ERK1/2 by suppressing MKP-1 and MKP-3 expression after γ-irradiation. These results indicate that ATP and ADP exhibit radioprotective effects by phosphorylation of ERK1/2 via activation of P2X7 and P2Y12 receptors, respectively, to promote γ-irradiation-induced DDR and DNA repair. ATP and ADP appear to be candidates for radioprotectants to reduce damage to non-cancerous cells during lung cancer radiotherapy by promoting DDR and DNA repair.

Rhizoma Bletillae polysaccharide elicits hemostatic effects in platelet-rich plasma by activating adenosine diphosphate receptor signaling pathway.

Rhizoma Bletillae, the tubes of Bletilla striata, has been traditionally used in China as a hemostatic agent. In preliminary studies, the major active fraction responsible for its hemostatic effect have been confirmed to be Rhizoma Bletillae polysaccharide (RBp), but the hemostatic mechanism of action of RBp is still unknown.The main aim of this study was to clarify its mechanism of hemostatic effect. RBp was prepared by 80 % ethanol precipitation of the water extract of Rhizoma Bletillae followed by the Sevag method to remove proteins. The average molecular weight (Mw) of the crude RBp maintained at a range of 30.06-200 KDa. The hemostatic effects of RBp were evaluated by testing its effect on the platelet aggregation of rat platelet-rich plasma (PRP). PRP was dealt with different concentrations of RBp and platelet aggregation was measured by the turbidimetric method. The hemostatic mechanism of RBp was investigated by examining its effect on platelet shape, platelet secretion, and activation of related receptors (P2Y1, P2Y12 and TXA2) by electron microscopy and the turbidimetric method. RBp significantly enhanced the platelet aggregations at concentrations of 50-200 mg/L in a concentration-dependent manner. The inhibitory rate of platelet aggregation was significantly increased by apyrase and Ro31-8220 in a concentration-dependent manner, while RBp-induced platelet aggregation was completely inhibited by P2Y1, P2Y12 and the PKC receptor antagonists. However, the aggregation was not sensitive to TXA2. RBp, the active ingredients of Rhizoma Bletillae responsible for its hemostatic effect, could significantly accelerate the platelet aggregation and shape change. The hemostatic mechanism may involve activation of the P2Y1, P2Y12, and PKC receptors in the adenosine diphosphate (ADP) receptor signaling pathway.

Effects of Dual Purinoceptor-dependent Approach on Release of Vascular Endothelial Growth Factor From Human Microvascular Endothelial Cell (HMEC-1) and Endothelial Cell Condition.

In the recent years, the awareness of the role purinergic signaling plays as a therapeutic target has increased considerably. The purinoceptor allows the action of extracellular nucleotides (P2 receptors) and intermediary products of their metabolism, such as adenosine (P1 receptors), regulating pivotal processes occurring in the cardiovascular system. This study focuses on a dual purinoreceptor-dependent approach, based on the activation of adenosine P1 receptors with the simultaneous inhibition of P2Y12 receptors that can be used as novel platelet inhibitors in antithrombotic therapy. Endothelial cells are directly exposed to the drugs circulating in the bloodstream. That is why effects of our concept on human microvascular endothelial cells (HMEC-1) were examined in in vitro studies, such as enzyme-linked immunosorbent assay and scratch assays. In response to adenosine receptor agonists, levels of secreted vascular endothelial growth factor varied. Two of them, 5'-N-ethylcarboxamidoadenosine and MRE0094 remarkably increased vascular endothelial growth factor release. The elevated levels were reduced when used together with the P2Y12 receptor antagonist. Also, rates of wound closure in a scratch assay were significantly reduced in these cases. The results suggest that the proposed treatment does not impair endothelial cell condition. In addition, it is suggested as a collateral benefit, namely solving the problem of excessive activation of endothelial cells during antiplatelet therapy.

sLRP1 (Soluble Low-Density Lipoprotein Receptor-Related Protein 1): A Novel Biomarker for P2Y12 (P2Y Purinoceptor 12) Receptor Expression in Atherosclerotic Plaques.

OBJECTIVE: Recent studies suggest that the P2Y12 (P2Y purinoceptor 12) receptor of vascular smooth muscle cells in atherosclerotic plaques aggravates atherosclerosis, and P2Y12 receptor inhibitors such as CDL (clopidogrel) may effectively treat atherosclerosis. It is imperative to identify an effective biomarker for reflecting the P2Y12 receptor expression on vascular smooth muscle cells in plaques. Approach and Results: We found that there was a positive correlation between the level of circulating sLRP1 (soluble low-density lipoprotein receptor-related protein 1) and the number of LRP1+ α-SMA+ (α-smooth muscle actin), P2Y12+, or P2Y12+ LRP1+ cells in plaques from apoE-/- mice fed a high-fat diet. Furthermore, activation of the P2Y12 receptor increased the expression and shedding of LRP1 in vascular smooth muscle cells by inhibiting cAMP (3'-5'-cyclic adenosine monophosphate)/PKA (protein kinase A)/SREBP-2 (sterol regulatory element binding transcription factor 2). Conversely, genetic knockdown or pharmacological inhibition of the P2Y12 receptor had the opposite effects. Additionally, CDL decreased the number of lesional LRP1+ α-SMA+ cells and the levels of circulating sLRP1 by activating cAMP/PKA/SREBP-2 in apoE-/- mice fed a high-fat diet. CONCLUSIONS: Our study suggests that sLRP1 may be a biomarker that reflects the P2Y12 receptor level in plaques and has the potential to be an indicator for administering P2Y12 receptor inhibitors for patients with atherosclerosis.

Duration of dual antiplatelet therapy after percutaneous coronary intervention with implantation of second-generation drug-eluting stent: A meta-analysis of randomized controlled trials.

Objective: The optimal duration of dual antiplatelet therapy (DAPT) in patients after PCI with implantation of a drugeluting stent is still controversial. We conducted a meta-analysis to compare the efficacy and safety of short term DAPT (≤ 3 months) followed by P2Y12 inhibitor monotherapy and standard DAPT (12 months) after PCI. Method: Relevant studies published in Medline, Embase, CoChrane Library were searched for randomized controlled trials (RCTs) until November 2019. Studies were screened by selection criteria then quality assessed through the Cochrane Collaboration's tool. Data were extracted from the included studies and statistically analyzed by RevMan 5.3 software. Results: Five RCTs (n=18,357) were included. Compared with standard DAPT, the short term DAPT was associated with a significant decrease in the major bleeding [odds ratio (OR)=0.43, 95% Confidence Interval (CI):0.32-0.58, P <0.00001] and any bleeding [OR=0.56, 95%CI:0.47-0.66, P<0.00001]. There were no significant differences in all-cause death [OR=0.91, 95%CI:0.71-1.16, P =0.45], major adverse cardiac and cerebrovascular event [OR=1.01, 95%CI:0.87-1.17, P =0.91] and stent thrombosis [OR=0.97, 95%CI:0.61-1.54, P =0.91] between with the short term DAPT group and the standard DAPT group. Conclusions: Short term DAPT followed by P2Y12 monotherapy could reduce the risk of bleeding without increasing the incidence of ischemic events after PCI with implantation of second-generation DES compared with standard DAPT. Therefore, short term DAPT may be a promising strategy to balance ischemic events and bleeding complications in patients after PCI.

Physician and Hospital Utilization of P2Y12 Inhibitors in ST-Segment-Elevation Myocardial Infarction in the United States: A Study From the National Cardiovascular Data Registry's Research to Practice Initiative.

Background Ticagrelor and prasugrel are potent P2Y12 inhibitors with superior efficacy compared with clopidogrel among patients with ST-segment-elevation myocardial infarction (STEMI), though use in recent practice is not well described. In this retrospective study, we assessed trends, predictors, and variation in use of P2Y12 inhibitors in patients with STEMI in the United States. Methods and Results We identified 169 505 STEMI patients in the Chest Pain-Myocardial Infarction Registry from October 2013 through March 2017. We determined national utilization rates of P2Y12 inhibitors at discharge, patient predictors for each medication, and variation in use between hospitals. In a subset of 9655 Medicare patients ≥65 years old, we compared 1-year adjusted risks of death, myocardial infarction, stroke, and bleeding based on hospital quartile of potent P2Y12 inhibitor use. Rates of ticagrelor use increased from 18.0% to 44.0%, while rates of prasugrel and clopidogrel use decreased from 24.6% to 13.5% and 57.4% to 42.6%, respectively. Prior percutaneous coronary intervention was the strongest clinical predictor for use of ticagrelor (adjusted odds ratio, 1.13 [95% CI, 1.09-1.18]) and prasugrel (adjusted odds ratio, 1.27 [95% CI, 1.21-1.34]) compared with clopidogrel. Predictors of clopidogrel use included no insurance, insurance with Medicare or Medicaid, and features associated with higher bleeding risk. The median hospital usage rate for newer P2Y12 inhibitors was 51.3% (interquartile range, 35.0%-65.9%), with substantial variation between hospitals (adjusted median odds ratio, 2.92 [95% CI, 2.77-3.10]). Among patients ≥65 years old, there were no differences in adjusted 1-year risks of adverse outcomes across hospital quartiles of potent P2Y12 inhibitor use. Conclusions Almost one-half of STEMI patients by 2017 were discharged on ticagrelor while far fewer received prasugrel. Patient characteristics are associated with P2Y12 inhibitor selection, though substantial hospital variation exists. Identifying barriers to use of more potent P2Y12 inhibitors may improve patient-centered decision-making for STEMI patients.

Impact of Continuous P2Y12 Inhibition Tailoring in Acute Coronary Syndrome and Genetically Impaired Clopidogrel Absorption.

Clopidogrel is still widely used in acute coronary syndrome despite the development of more potent P2Y12 inhibitors. Previously, we conducted a trial that evaluated serial clopidogrel dose adjustment based on platelet function testing in acute coronary syndrome patients with initial high on-treatment platelet reactivity (HTPR). In this substudy, we performed post hoc analysis of the effect of ABCB1 genetic variants C3435T and G2677T/A on platelet inhibition and outcomes. There were no differences in the proportion of HTPR patients among C3435T carriers and noncarriers in both interventional and control group. G2677T carriers expressed significantly higher proportion of HTPR pattern throughout 12-month follow-up in the control group with no difference in the interventional group. There was no difference in ischemic outcomes between C3435T and G2677T carriers and noncarriers in both groups of patients. The results indicate that ABCB1 genotyping is not useful to guide clopidogrel therapy tailoring to improve high-risk patient management.

Laboratory assessments of therapeutic platelet inhibition in endovascular neurosurgery: complication prediction using the VerifyNow P2Y12 assay and thromboelastography with platelet mapping.

OBJECTIVE: Inhibition of platelet aggregation is universally used to prevent thromboembolic complications related to stent placement in endovascular neurosurgery, but excessive inhibition potentiates hemorrhagic complications. Previously, the authors demonstrated that two different commercially available measures of adenosine diphosphate (ADP)-dependent platelet inhibition-the VerifyNow P2Y12 clopidogrel assay (measured in platelet reactivity units [PRU]) and maximal amplitude (MA) attributable to ADP activity (MA-ADP) derived from thromboelastography (TEG) with platelet mapping (PM)-yielded wildly different results. This study sought to analyze observed complications to quantify the ideal therapeutic windows for both tests. METHODS: Ninety-one patients with simultaneous or near-simultaneous PRU and TEG-PM results who underwent craniocervical endovascular stenting at the authors' institution between September 2015 and November 2017 were identified and retrospectively enrolled. From November 2017 until June 2019, 109 additional patients were prospectively enrolled. For this study, in-hospital thrombotic and hemorrhagic complications (both CNS and non-CNS) were tabulated, and receiver operating characteristic (ROC) curve analysis was used to identify threshold values of the PRU and MA-ADP for predicting each type of complication. RESULTS: Of the 200 patients enrolled, 7 were excluded because of anemia or thrombocytopenia outside of the test manufacturer's specified ranges and 1 was excluded because they did not have a TEG-PM result. Including complications of all severities, there were a total of 15 CNS thrombotic complications, 1 access-site thrombotic complication, 3 CNS hemorrhages, 8 access-site hemorrhagic complications, and 3 hemorrhagic complications not affecting either the CNS or the access site. ROC curve analysis yielded therapeutic threshold values of 118-144 PRU. The results demonstrated PRU has a significant dose-dependent effect on the rates of thrombosis and hemorrhage. Logistic regression models did not demonstrate statistically significant relationships between the MA-ADP and either thrombosis or hemorrhage. ROC analysis based on these models is of little value and did not identify significant threshold values for MA-ADP. CONCLUSIONS: There continues to be poor correlation between the results of TEG-PM and PRU. PRU accurately predicted complications, with a relatively narrow ideal value range of 118-144. The MA-ADP alone does not appear able to accurately predict either hemorrhagic or thrombotic complications in this group.

A Pharmacodynamic Study of CN-218, a Novel Antiplatelet and Antithrombotic Agent Primarily Targeting the P2Y12 Receptor.

PURPOSE: Drugs inhibiting the platelet P2Y12 receptor, such as clopidogrel and prasugrel, are potent antithrombotic agents and are widely used in cardiovascular disease. However, the adverse effects of these drugs have limited their clinical use. For example, clopidogrel resistance occurs in approximately one third of patients, while prasugrel increases the risk of major bleeding. Therefore, new generations of such drugs are of clinical interest. METHODS: In this study, the pharmacodynamics of a new P2Y12 antagonist, CN-218, was compared with that of clopidogrel and prasugrel in rats and mice. The differences between CN-218 and clopidogrel include deuteration of the 7-position methyl carboxylate and the introduction of cinnamate in the 2-position of thiophene. RESULTS: CN-218 had an antiaggregatory efficacy that was at least five times more potent than that of clopidogrel but not as potent as that of prasugrel. It had a significant impact on activated partial thromboplastin time (APTT), whereby the APTT of CN-218-treated rats was approximately 9 s longer than that of the vehicle- or clopidogrel-treated group, while it had no impact on prothrombin time (PT) in rats. CN-218 had a similar potent antithrombotic effect to that of prasugrel and clopidogrel and also reduced the risk of bleeding compared to prasugrel. CONCLUSION: CN-218 may be a promising antithrombotic agent, with potent antiplatelet and significant anticoagulant activity, as well as a lower risk of bleeding compared to clopidogrel and prasugrel.

The efficacy and safety of P2Y12 inhibitor monotherapy in patients after percutaneous coronary intervention.

The optimal antiplatelet therapy after percutaneous coronary intervention (PCI) remains to be elucidated. Monotherapy with a P2Y12 inhibitor may be inferior to dual antiplatelet therapy in patients after PCI. PubMed, EMBASE (by Ovidsp), Web of Science, and The Cochrane Library were searched from database inception to 2 October 2019. The composite of cardiovascular outcomes, all-cause mortality, myocardial infarction (MI), stroke, stent thrombosis, and major bleeding were evaluated. Pooled outcomes were presented as relative risk (RR) and 95% confidence intervals (CIs). A total of four trials randomizing 29 089 participants were included. Compared with the dual antiplatelet therapy group (n = 14 559), the P2Y12 inhibitor monotherapy group (n = 14 530) significantly decreased the incidence of bleeding events (2.0% vs 3.1%; RR: 0.60; 95% CI: 0.43-0.84; P = .005). There were no significant differences in all-cause mortality (1.3% vs 1.5%; RR: 0.87; 95% CI, 0.71-1.06; P = .16), myocardial infarction (2.1% vs 1.9%; RR, 1.06; 95% CI, 0.90-1.25; P = .46), stroke (0.6% vs 0.5%; RR, 1.18; 95% CI, 0.67-2.07; P = .57), or stent thrombosis (0.5% vs 0.4%; RR, 1.14; 95% CI, 0.81-1.61; P = .44) between the two groups. P2Y12 inhibitor monotherapy did not show any significant difference in the adverse cardiac and cerebrovascular events, but markedly decreased the risk of bleeding among patients after PCI vs dual antiplatelet therapy. However, it still needs to be further confirmed due to limited data.

What Are Optimal P2Y12 Inhibitor and Schedule of Administration in Patients With Acute Coronary Syndrome?

Guidelines recommend treatment with a P2Y12 platelet adenosine diphosphate receptor inhibitor in patients undergoing elective or urgent percutaneous coronary intervention (PCI), but the optimal agent or timing of administration is still not clearly specified. The P2Y12 inhibitor was initially used for its platelet anti-aggregatory action to block thrombosis of the recanalized coronary artery or deployed stent. It is now recognized that these agents also offer potent cardioprotection against a reperfusion injury that occurs in the first minutes of reperfusion if platelet aggregation is blocked at the time of reperfusion. But this is difficult to achieve with oral agents which are slowly absorbed and often require time-consuming metabolic activation. Patients with ST-segment elevation myocardial infarction who usually have a large mass of myocardium at risk of infarction seldom have sufficient time for upstream-administered oral agents to achieve a therapeutic P2Y12 level of inhibition by the time of balloon inflation. However, optimal treatment could be assured by initiating an IV cangrelor infusion shortly prior to stenting followed by subsequent post-PCI transition to an oral agent, that is, ticagrelor, once success of the recanalization and absence of need for surgical intervention are confirmed. Not only should this sequence provide optimal protection against infarction, it should also negate bleeding if coronary artery bypass grafting should be required since stopping the cangrelor infusion at any time will quickly restore platelet reactivity. It is anticipated that cangrelor-induced myocardial salvage will help preserve myocardial function and significantly diminish postinfarction heart failure.