Ticagrelor Treatment Research Articles

Rationale and Design of the High Platelet Inhibition with Ticagrelor to Improve Left Ventricular Remodeling in Patients with ST-Segment Elevation Myocardial Infarction (HEALING-AMI) Trial

Background and ObjectivesImpaired recovery from left ventricular (LV) dysfunction is a major prognostic factor after myocardial infarction (MI). Because P2Y12 receptor blockade inhibits myocardial injury, ticagrelor with off-target properties may have myocardial protection over clopidogrel. In animal models, ticagrelor vs. clopidogrel protects myocardium against reperfusion injury and improves remodeling after MI. We aimed to investigate the effect of ticagrelor on sequential myocardial remodeling process after MI.MethodsHigh platelet inhibition with ticagrelor to improve LV remodeling in patients with ST-segment elevation MI (HEALING-AMI) is an investigator-initiated, randomized, open-label, assessor-blinded, multi-center trial done at 10 sites in Korea. Patients will be enrolled if they have ST-segment elevation MI (STEMI) treated with primary percutaneous coronary intervention and a planned duration of dual antiplatelet treatment of at least 6 months. Screened patients will be randomly assigned (1:1) using an internet-based randomization with a computer-generated blocking with stratification across study sites to either ticagrelor or clopidogrel treatment. The co-primary primary endpoints are LV remodeling index with three-dimensional echocardiography and the level of N-terminal prohormone B-type natriuretic peptide (NT-proBNP) at 6 months representing post-MI remodeling processes. Changes of LV end-systolic/diastolic volume indices and LV ejection fraction between baseline and 6-month follow-up will be also evaluated. Analysis is per protocol.ConclusionsHEALING-AMI is testing the effect of ticagrelor in reducing adverse LV remodeling following STEMI. Our trial would show the benefit of ticagrelor vs. clopidogrel related to the recovery of post-MI LV dysfunction beyond potent platelet inhibition.Trial RegistrationClinicalTrials.gov Identifier: NCT02224534

ANTIPLATELET ADEQUACY OF CYCLOPENTYL TRIAZOLOPYRIMIDINE VERSUS CLOPIDOGREL IN-PATIENTS WITH CORONARY HEART DISEASE

Objective: Ticagrelor, cyclopentyl triazolopyrimidine drug, and Clopidogrel, second-generation thienopyridine drug are antiplatelet drugs indicated for the prevention of thrombotic events in patients with acute or chronic coronary syndromes. The aim of this study is to assess efficacy and safety outcomes of ticagrelor treatment versus Clopidogrel treatment in patients with stable coronary artery disease (stable angina) using maximal platelet aggregation percent (MPAP) method and platelet reactivity index percent (PRIP) method.Methods: A total of 42 patients (27 male and 15 female), their ages ranging (48±8) years with stable angina enrolled from Ibn Albitar Center for Cardiac Surgery for this crossover study. After satisfying, the properties of inclusion criteria they screened for clopidogrel treatment 75 mg daily for 2 weeks than after 2 weeks periods of wash off they treated with ticagrelor 90 mg twice daily for another 2 weeks. Platelet reactivity was tested at baseline (before treatment), after 2 weeks treatment with clopidogrel and after another 2 weeks treatment with ticagrelor. Platelet reactivity measured by light transmittance aggregometry test and by vasodilator-stimulated phosphoprotein (VASP) phosphorylation test.Results: The results of MPAP after 2 weeks treatment with clopidogrel or ticagrelor showed high significant reduction in platelet aggregation in patients with ticagrelor treatment as compared to clopidogrel treatment (30±6% vs. 44±8%). As well, the results of PRIP using VASP-phosphorylation after 2 weeks treatment with clopidogrel or ticagrelor showed high significant reduction in platelet aggregation in patients with ticagrelor treatment as compared to clopidogrel treatment (22±5% vs. 36±7%).Conclusion: Treatment with ticagrelor produced a reduction in platelet reactivity consistent with the reduction in major adverse cardiovascular events and improved survival without increasing major bleeding.

Ticagrelor Induced Platelet Dysfunction Can be Assessed Under Shear Conditions and Correction By Platelets Is Influenced By Storage Temperature

Introduction:The use of antiplatelet (anti-PLT) drugs for prophylaxis and treatment of cardiovascular disease continues to rise. A significant problem with these medications is increased bleeding, which can be life threatening. Strategies to manage bleeding whilst on anti-PLT medication are limited and often include PLT transfusion. Evidence of efficacy is lacking, and it is not known whether storage conditions affect outcome. We sought to study this clinical problem using an in vitro system that simulates in vivo shear forces. We assessed PLT adhesion to collagen under arterial shear conditions in whole blood (WB) treated with Ticagrelor, a P2Y12 inhibitor. We tested the hypothesis that the storage temperature of PLTs would affect their ability to correct Ticagrelor-induced platelet dysfunction.Methods:WB was collectedand treated with a therapeutic concentration of Ticagrelor (1.0µM). After a 15 min incubation the treated WB was dosed with apheresis platelets (AP) to simulate PLT transfusion. The AP used were collected as hyperconcentrated double units from different healthy donors (n=3), diluted with T-PAS+ (65% T-PAS+, 35% plasma), and split equally amongst two bags. One bag was stored at room temperature (22±2°C; RTP) with agitation, and the other bag was cold-stored (4±2°C; CSP) without agitation. Ticagrelor-treated WB was dosed with RTP and CSP in increments equivalent to 1, 2, and 3 times the adult therapeutic doses (ATD) of PLTs (calculated using a 70kg person with a circulating blood volume of 5000ml) stored for 0 (fresh), 3, 7 and 10 days. Random WB donors were selected who were ABO RhD compatible with the AP unit.Bioflux 1000 (Fluxion) was used to evaluate PLT function of the treated and dosed WB. Briefly, WB (treated or dosed) was labelled with calcein and perfused through a collagen-coated chamber under arterial shear (19.83 dyn/cm2) for 10 min. PLT adhesion to collagen was recorded for 10 min, with images obtained every 30s. Fluorescence intensity and the percentage of area covered was determined using BioFlux Montage Software. Data was analysed and the t-test performed using GraphPad Prism version 7.Prior to dosing, RTP and CSP bags were analysed at each timepoint visually for aggregates and ‘swirl’, PLT count (HORIBA MICROS 60), light transmission aggregometry (Chronolog 700, agonists; ADP [10µM] and AA [0.5mM]) and chemistry (iSTAT, CG4+ cartridge).Results:PLT counts dropped in both CSP and RTP but were not significantly different at any timepoint (Fig. 1A). PLT aggregation to ADP negligible after day 3 in RTP but was well maintained in the CSP out to 10 days (p<0.03) (Fig. 1B). pH decreased in CSP and increased in RTP but did not reach significance (p=0.07). Lactate was significantly higher in RTP compared to CSP at day 10 (p=0.01) (Fig. 1D). Increments in PLT count in treated WB were lower with doses of CSP than RTP, with the mean increases of 10x106/ml and 26x106/ml per ATD respectively.For Bioflux runs, Ticagrelor treatment lowered PLT adhesion to collagen by 40-66% compared to control (WB treated with DMSO 0.1%) after 10 min of perfusion. On Day 0, PLT adhesion increased with increasing doses of fresh PLTs. At Day 3 of storage, both CSP and RTP performed equally. By day 7, CSP showed enhanced adhesion and aggregation to collagen compared to RTP, both continuing to exhibit a dose effect, with 1 dose of CSP being superior to 3 ATD RTP in all 3 donors. CSP-dosed samples effectively rescued Ticagrelor-treated WB out to 10 days storage. Addition of RTP stored beyond 7 days had a detrimental effect (i.e. lower adhesion than Ticagrelor treatment alone).Conclusions:This study has demonstrated that the anti-PLT effects of Ticagrelor can be observed and quantified under physiologic flow conditions using a BioFlux system and that these effects can be overcome using PLT transfusion in a dose-dependent manner. The storage temperature of AP affects their ability to rescue Ticagrelor-induced PLT dysfunction under shear conditions with cold storage providing better rescue of dysfunction than RTP even out to 10 days of storage. Further work is needed to assess the ability of PLT concentrates to rescue other causes of PLT dysfunction and to reduce bleeding. DisclosuresNo relevant conflicts of interest to declare.

Ischemic stroke rates decrease with increased ticagrelor use after acute myocardial infarction in patients treated with percutaneous coronary intervention.

Aims It is unknown whether dual antiplatelet therapy with ticagrelor instead of clopidogrel reduces the risk of ischaemic stroke in acute myocardial infarction patients that undergo percutaneous coronary intervention. This study investigated whether the introduction of dual antiplatelet therapy with ticagrelor was associated with reduced ischaemic stroke risk in a real-world population. Methods and results Patients with ischaemic stroke after acute myocardial infarction from 8 December 2009-31 December 2013 were identified using the Register for Information and Knowledge on Swedish Heart Intensive Care Admissions and the Swedish National Patient Register. The study period was divided into two similar periods using the date of the first prescription of ticagrelor as the cut-off. The risk of ischaemic stroke in percutaneous coronary intervention-treated acute myocardial infarction patients during the first period (100% clopidogrel treatment) versus the second period (60.7% ticagrelor treatment) was assessed using Kaplan-Meier analysis. Variables associated with ischaemic stroke were identified using a multivariable Cox proportional hazards model. There were 686 ischaemic stroke events (2.0%) among 34931 percutaneous coronary intervention-treated acute myocardial infarction patients within one year, 366 (2.2%) during the first period and 320 (1.8%) during the second period ( p = 0.004). The Cox model showed a 21% relative risk reduction in ischaemic stroke in the second period versus the first one (hazard ratio 0.79, 95% confidence interval, 0.68-0.92; p = 0.003). The independent predictors of increased stroke risk were older age, hypertension, diabetes mellitus, atrial fibrillation, heart failure during hospitalization, previous ischaemic stroke, and ST-segment elevation myocardial infarction. Conclusion The risk of ischaemic stroke in percutaneous coronary intervention-treated acute myocardial infarction patients decreased after the introduction of ticagrelor in Sweden.

Efficacy and Safety of Ticagrelor in Relation to Aspirin Use Within the Week Before Randomization in the SOCRATES Trial.

SOCRATES (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes), comparing ticagrelor with aspirin in patients with acute cerebral ischemia, found a nonsignificant 11% relative risk reduction for stroke, myocardial infarction, or death (P=0.07). Aspirin intake before randomization could enhance the effect of ticagrelor by conferring dual antiplatelet effect during a high-risk period for subsequent stroke. Therefore, we explored the efficacy and safety of ticagrelor versus aspirin in the patients who received any aspirin the week before randomization. A prespecified subgroup analysis in SOCRATES (n=13 199), randomizing patients with acute ischemic stroke (National Institutes of Health Stroke Scale score of ≤5) or transient ischemic attack (ABCD2 score of ≥4) to 90-day treatment with ticagrelor or aspirin. Patients in the prior-aspirin group had received any aspirin within the week before randomization. Primary end point was time to stroke, myocardial infarction, or death. Safety end point was PLATO (Study of Platelet Inhibition and Patient Outcomes) major bleeding. The 4232 patients in the prior-aspirin group were older, had more vascular risk factors, and vascular disease than the other patients. In the prior-aspirin group, the primary end point occurred in 138/2130 (6.5%) of patients on ticagrelor and in 177/2102 (8.3%) on aspirin (hazard ratio, 0.76; 95% confidence interval, 0.61-0.95; P=0.02); in patients with no prior-aspirin usage an event occurred in 304/4459 (6.9%) and 320/4508 (7.1%) on ticagrelor and aspirin, respectively (hazard ratio, 0.96; 95% confidence interval, 0.82-1.12; P=0.59). The treatment-by-prior-aspirin interaction was not statistically significant (P=0.10). In the prior-aspirin group, major bleeding occurred in 0.7% and 0.4% of patients on ticagrelor and aspirin, respectively (hazard ratio, 1.58; 95% confidence interval, 0.68-3.65; P=0.28). In this secondary analysis from SOCRATES, fewer primary end points occurred on ticagrelor treatment than on aspirin in patients receiving aspirin before randomization, but there was no significant treatment-by-prior-aspirin interaction. A new study will investigate the benefit-risk of combining ticagrelor and aspirin in patients with acute cerebral ischemia (URL: https://www.clinicaltrials.gov. Unique identifier: NCT03354429). URL: https://www.clinicaltrials.gov. Unique identifier: NCT01994720.

Prevalence, long-term prognosis and medical alternatives for patients admitted for acute coronary syndromes and prasugrel contraindication

BackgroundPrasugrel is a potent antiplatelet therapy that has demonstrated to be superior to clopidogrel for patients with acute coronary syndromes (ACS) but has three main contraindications. MethodsProspective study of all patients admitted for ACS in two hospitals. Prasugrel contraindication group was defined by the presence of age >75 years, weight <60 kg or previous stroke. We also performed a propensity score matching to obtain a well-balanced subset of patients with the same probability of receiving ticagrelor. ResultsWe included 8207 patients and 2538 (30.9%) had any contraindication for prasugrel, being age >75 years the most frequent (29.0%). Hospital mortality was 4.4% and it was >2-fold higher in patients with any contraindication for prasugrel (7.9% vs. 2.8%; p < 0.01). Postdischarge follow-up (median 59.9 months) revealed that patients with prasugrel contraindication had higher cardiovascular and all-cause mortality as well as a first major cardiovascular event (MACE). No differences in bleeding rates were found in patients with vs. without prasugrel contraindication. Prasugrel contraindication was independently associated to higher cardiovascular (HR: 1.42) and all-cause mortality (HR: 1.47), as well as higher MACE (HR: 1.25). In the sub-cohort of 482 pairs of patients, obtained by a propensity score matching, ticagrelor treatment was associated with lower cardiovascular death (HR: 0.22), all-cause mortality (HR: 0.30) and first MACE (HR: 0.58) in patients with prasugrel contraindication. ConclusionsAlmost one third of ACS patients have prasugrel contraindications and they have worst in in-hospital and post-discharge prognosis. Ticagrelor improved postdischarge outcomes in patients with prasugrel contraindications.

Ticagrelor-related late-onset dyspnea as cause of emergency department visit: a 3-year outpatient study.

The aim of the current study was to define the rate of emergency department visits for late-onset dyspnea in acute coronary syndrome patients treated with ticagrelor. We conducted a population-based study on about 850 000 residents of Florence metropolitan area, by using data from healthcare records. Between 2012 and 2014, 1073 subjects in Florence metropolitan area had at least one prescription of ticagrelor. Two-hundred and thirty-four patients were diagnosed with 'respiratory system or other chest symptoms' or 'other diseases of lung', and among them we identified 20 subjects with ticagrelor-related late-onset dyspnea. These, and the 979 nonevent subjects (receiving ticagrelor but not developing dyspnea), contributed to 413 person-years overall. The dyspnea rate was 4.84 per 100 person-years (95% confidence interval: 3.12-7.51). Late-onset dyspnea rate is notably lower than early-onset one; nevertheless prescribing clinicians should be aware that about one in 20 outpatients with a stabilized ticagrelor treatment might develop a dyspnea leading to an emergency department visit, and they should consider ticagrelor replacement only in patients who cannot tolerate dyspnea.

Comparison of antiplatelet treatment in patients with clopidogrel nonresponders with or without carriage of CYP2C19 polymorphism.

Several interventions exist for overcoming high platelet reactivity (HPR) on clopidogrel therapy. The goal of this study was to identify strategies that improve inhibition of platelet reactivity in clopidogrel nonresponders with or without loss of function CYP2C19 genotypes, resulting in platelet reactivity similar to that in responders. A total of 376 patients with stenting for coronary artery disease underwent platelet function testing in three centers. Blinded platelet function tests were performed after 75 mg daily clopidogrel treatment for 28 days. In total, 183 nonresponders were genotyped, were randomized to four treatment groups with each treatment lasting approximately 28 days, and underwent repeated measurements of platelet reactivity after treatment. With 75 mg of daily clopidogrel, nonresponders had significantly higher HPR than did responders (multiple electrode aggregometry [MEA, arbitrary platelet aggregation unit]: mean, 71.4; 95% confidence intervals [CI], 68.6 to 74.3; and mean, 27.5; 95% CI, 26.0 to 28.9, respectively; p < 0.001). Ticagrelor or ticlopidine treatment in nonresponders resulted in platelet reactivity similar to that in responders in intermediate metabolizers (mean, 24.0; 95% CI, 19.6 to 28.4; p > 0.05; and mean, 30.0; 95% CI, 24.7 to 37.5; p > 0.05, respectively) and poor metabolizers (mean, 23.2; 95% CI, 18.0 to 28.3; p > 0.05; and mean, 30.3; 95% CI, 24.5 to 6.0; p > 0.05, respectively). However, in extensive metabolizers, only ticagrelor treatment showed platelet reactivity similar to that in responders (mean, 26.1; 95% CI, 24.1 to 28.0; p > 0.05). Among clopidogrel nonresponders with cardiovascular disease on 75 mg daily clopidogrel, ticagrelor resulted in a comparable degree of platelet inhibition in all nonresponders compared with 150 mg daily clopidogrel or triple therapy with clopidogrel and cilostazol, irrespective of phenotype.

Ticagrelor protects against AngII-induced endothelial dysfunction by alleviating endoplasmic reticulum stress

Ticagrelor has been reported to decrease cardiovascular mortality compared with clopidogrel. This benefit cannot be fully explained by the more efficient platelet inhibition. Many studies demonstrated that ticagrelor improved endothelial function, leaving the mechanism elusive though. The present study aims to investigate whether ticagrelor protects against endothelial dysfunction induced by angiotensinII (AngII) through alleviating endoplasmic reticulum (ER) stress. Male Sprague Dawley rats were infused with AngII or vehicle and administrated with ticagrelor or vehicle for 14 days. Reactive oxygen species (ROS) was detected. Aortas from normal mice were incubated with endoplasmic reticulum stress inducer tunicamycin with or without ticagrelor. Vasorecactivity was measured on wire myography. Rat aortic endothelial cells (RAECs) were pretreated with ticagrelor followed by AngII or tunicamycin. Endothelial nitric oxide synthase (eNOS) phosphorylation and ER stress markers were determined by western blotting. Impaired endothelial function, induction of ER stress, reduced eNOS phosphorylation and elevated ROS generation was restored by ticagrelor treatment in vivo. In addition, tunicamycin induced endothelial dysfunction was improved by ticagrelor. In vitro, the induction of ER stress and inhibited eNOS phosphorylation in REACs exposed to AngII as well as tunicamycin was reversed by co-culturing with ticagrelor. In conclusion, ticagrelor protects against AngII-induced endothelial dysfunction via alleviating ER stress.

Ticagrelor attenuates myocardial ischaemia-reperfusion injury possibly through downregulating galectin-3 expression in the infarct area of rats.

AimsThe full benefits of myocardial revascularization strategies applied to acute myocardial infarction patients might be reduced by myocardial ischaemia and reperfusion (I/R) injury. It is known that inflammation plays an important role in the pathogenesis of I/R injury and galectin‐3, a known inflammatory factor, is actively involved in ischaemia‐induced inflammation and fibrosis of various organs. Previous studies demonstrated that anti‐platelets therapy with ticagrelor, a new P2Y12 receptor antagonist, could effectively attenuate myocardial I/R injury and I/R injury‐related inflammatory responses. It remains unknown whether the cardioprotective effects of ticagrelor are also mediated by modulating myocardial galectin‐3 expression.MethodsWe determined the ratio of infarct area (IA)/area at risk (AAR), expression of galectin‐3, TNF‐α and IL‐6 in infarct area of rats treated with placebo (equal volume saline per gastric gavage immediately after LAD ligation, then once daily till study end) or ticagrelor (150 mg kg−1 dissolved in saline per gastric gavage immediately after LAD ligation, then once daily till study end) at 24 h, 3 and 7 days post I (45 min)/R injury. Sham‐operated rats served as control.ResultsOur results showed that ticagrelor treatment significantly reduced IA/AAR ratio at 3 and 7 days post I/R, downregulated mRNA and protein expression of galectin‐3, as well as mRNA expression of TNF‐α and IL‐6 in infarct area at 24 h, 3 and 7 days post I/R.ConclusionsOur results suggest that the cardioprotective effects of ticagrelor might partly be mediated by downregulating galectin‐3 expression in infarct area in this rat model of myocardial I/R injury.

Population pharmacokinetics and pharmacodynamics of ticagrelor and AR-C124910XX in Chinese healthy male subjects.

Ticagrelor, the first reversible P2Y12 receptor antagonist, exhibits faster onset and offset of antiplatelet effects and more consistent platelet inhibition than clopidogrel in both healthy subjects and patients with stable coronary artery disease. The objectives of this study were to establish a population pharmacokinetics (PK) and pharmacodynamics (PD) model of ticagrelor and to provide a theoretical basis for the optimization of ticagrelor treatment in clinic. A single oral dose of 180mg ticagrelor was administered to 14 healthy male subjects in a randomized study. Common single-nucleotide polymorphisms (SNPs) in biotransformation enzymes CYP3A4 and CYP3A5 (CYP3A4*1G and CYP3A5*3) were genotyped by PCR-direct sequencing. Blood samples were collected to measure plasma concentrations of ticagrelor and its active metabolite AR-C124910XX and maximal platelet inhibition. Various models were evaluated to characterize the pharmacokinetics of ticagrelor and AR-C124910XX as well as their PK-PD relationship. Covariates that may potentially affect PK or PD of ticagrelor and AR-C124910XX were included and assessed. Simulation for dosage regimen was performed based on the final PK-PD model. Ticagrelor and AR-C124910XX PK were best described by a two-compartment model with first-order transit absorption model. CYP3A4*1G increased clearance for AR-C124910XX, but had no significant effect on ticagrelor clearance. The relationship between concentration and platelet response of ticagrelor was best described by a turnover model. Simulation results indicated that a lower dosage regimen of 30mg maintenance dose (MD) could produce an anticipated anti-platelet response in comparison to the routine clinical dosage regimen (180mg loading dose (LD), 90mg MD). Our study developed a population PK-PD model for ticagrelor and further simulation for dosage regimen was performed based on the final model. Compared to the current recommended dosage regimen (180mg LD, 90mg MD), our simulation result of a relatively lower dose (30mg MD) could also obtain an acceptable anti-platelet response, which may provide a reference for further dosage regimen design in Chinese population.

Safety and Incidence of Cardiovascular Events in Chinese Patients with Acute Coronary Syndrome Treated with Ticagrelor: the 12-Month, Phase IV, Multicenter, Single-Arm DAYU Study

PurposeTicagrelor is an orally administered, reversibly binding, direct-acting P2Y12 receptor antagonist previously evaluated in several phase III trials. This phase IV, multicenter, single-arm trial assessed the safety and incidence of cardiovascular (CV) events with ticagrelor in Chinese patients experiencing an acute coronary syndrome (ACS).MethodsPatients hospitalized with an ACS received ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) plus low-dose aspirin (75–100 mg/day) for up to 12 months. Safety was evaluated via PLATO-defined bleeding events, adverse events (AEs), serious AEs, and laboratory measurements. The incidence of major CV events was also evaluated.ResultsThe safety population included 2001 patients. During ticagrelor treatment, 426 (21.3%) patients had at least one PLATO-defined bleeding AE, mainly minimal bleedings (n = 333). Major bleeding events occurred in 27 (1.3%) patients, including fatal/life-threatening bleeding in 17 (0.8%) patients and other major bleeding in 11 (0.5%) patients, with a Kaplan-Meier estimate of patients with the event (95% CI) of 1.6% (1.1–2.3%). In total, 784 (39.2%) patients had at least one non-bleeding AE, the majority of which were mild in severity. The composite endpoint of CV death, myocardial infarction, and stroke occurred in 83 (4.1%) patients.ConclusionsTicagrelor plus low-dose aspirin for up to 1 year was associated with a low rate of major bleeding events and a low incidence of major CV events (CV death, myocardial infarction, stroke) in Chinese patients with ACS. The overall safety profile of ticagrelor in this population was in line with current prescribing information.

Ticagrelor for Secondary Prevention of Atherothrombotic Events in Patients With Multivessel Coronary Disease

BackgroundPatients with prior myocardial infarction (MI) and multivessel coronary disease (MVD) are at high risk for recurrent coronary events. ObjectivesThe authors investigated the efficacy and safety of ticagrelor versus placebo in patients with MVD in the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In Myocardial Infarction 54) trial. MethodsPatients with a history of MI 1 to 3 years before inclusion in the PEGASUS-TIMI 54 trial were stratified in a pre-specified analysis based on the presence of MVD. The effect of ticagrelor (60 mg and 90 mg) on the composite of cardiovascular death, MI, or stroke (major adverse cardiovascular events [MACE]), as well as the composite of coronary death, MI, or stent thrombosis (coronary events), and on TIMI major bleeding, intracranial hemorrhage (ICH), and fatal bleeding were evaluated over a median of 33 months. ResultsA total of 12,558 patients (59.4%) had MVD. In the placebo arm, compared with patients without MVD, those with MVD were at higher risk for MACE (9.37% vs. 8.57%, adjusted hazard ratio [HRadj]: 1.24; p = 0.026) and for coronary events (7.67% vs. 5.34%, HRadj: 1.49; p = 0.0005). In patients with MVD, ticagrelor reduced the risk of MACE (7.94% vs. 9.37%, HR: 0.82; p = 0.004) and coronary events (6.02% vs. 7.67%, HR: 0.76; p < 0.0001), including a 36% reduction in coronary death (HR: 0.64; 95% confidence interval: 0.48 to 0.85; p = 0.002). In this subgroup, ticagrelor increased the risk of TIMI major bleeding (2.52% vs. 1.08%, HR: 2.67; p < 0.0001), but not ICH or fatal bleeds. ConclusionsPatients with prior MI and MVD are at increased risk of MACE and coronary events, and experience substantial relative and absolute risk reductions in both outcomes with long-term ticagrelor treatment relative to those without MVD. Ticagrelor increases the risk of TIMI major bleeding, but not ICH or fatal bleeding. For patients with prior MI and MVD, ticagrelor is an effective option for long-term antiplatelet therapy. (Prevention of Cardiovascular Events [e.g., Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS]; NCT01225562)

Design and Rationale for comParison Between ticagreLor and clopidogrEl on mIcrocirculation in Patients with Acute cOronary Syndrome Undergoing Percutaneous Coronary Intervention (PLEIO) Trial

It has been previously demonstrated that ticagrelor can reduce mortality compared to clopidogrel in acute coronary syndrome (ACS) patients. However, the mechanism for this mortality reduction remains uncertain. The objective of the present study is to assess the impact of chronic ticagrelor treatment on microvascular circulation. A total of 120 participants aged 20–85 years with clinical diagnosis of ACS will be randomized in a 1:1 fashion to the following two groups: ticagrelor 90 mg twice daily; clopidogrel 75 mg once daily. To evaluate the status of microcirculation, the primary end point is coronary microvascular dysfunction measured using an index of microcirculatory resistance (IMR) at 6 months after receiving the study agent. The purpose of this trial is to investigate whether ticagrelor, beyond its antiplatelet efficacy, could improve coronary microcirculation more effectively than clopidogrel for patients with ACS.

Ticagrelor inhibits platelet-tumor cell interactions and metastasis in human and murine breast cancer.

Activated platelets promote the proliferation and metastatic potential of cancer cells. Platelet activation is largely mediated through ADP engagement of purinergic P2Y12 receptors on platelets. We examined the potential of the reversible P2Y12 inhibitor ticagrelor, an agent used clinically to prevent cardiovascular and cerebrovascular events, to reduce tumor growth and metastasis. In vitro, MCF-7, MDA-MB-468, and MDA-MB-231 human mammary carcinoma cells exhibited decreased interaction with platelets treated with ticagrelor compared to untreated platelets. Prevention of tumor cell-platelet interactions through pretreatment of platelets with ticagrelor did not improve natural killer cell-mediated tumor cell killing of K562 myelogenous leukemia target cells. Additionally, ticagrelor had no effect on proliferation of 4T1 mouse mammary carcinoma cells co-cultured with platelets, or on primary 4T1 tumor growth. In an orthotopic 4T1 breast cancer model, ticagrelor (10mg/kg), but not clopidogrel (10mg/kg) or saline, resulted in reduced metastasis and improved survival. Ticagrelor treatment was associated with a marked reduction in tumor cell-platelet aggregates in the lungs at 10, 30 and 60min post-intravenous inoculation. These findings suggest a role for P2Y12-mediated platelet activation in promoting metastasis, and provide support for the use of ticagrelor in the prevention of breast cancer spread.

Short-term coronary physiology parameters evolution in acute coronary syndrome patients with multivessel disease treated with ticagrelor

Ticagrelor increases adenosine plasma concentration in acute coronary syndrome patients (ACS) by inhibiting adenosine uptake by red blood cells. Besides, ticagrelor treatment might be more effective than clopidogrel in reducing microvascular injury in ST-elevation myocardial infarction (STEMI) patients. However, the effects of ticagrelor on coronary physiology parameters in ACS patients with multivessel disease (MVD) remain uncertain. We designed a prospective study to assess the effects of ticagrelor treatment on microvascular resistance in ASC patients with MVD. Ten consecutive non-STE-ASC patients with no prior ticagrelor treatment and MVD, defined as the presence of at least one significant (> 50%) lesion in a non-infarct related artery, underwent intracoronary physiology parameters assessment immediately after primary percutaneous coronary intervention (PCI) of the culprit lesion. A second series of measurements was performed after 72 hours of ticagrelor treatment. The primary endpoint was the index of microvascular resistance (IMR) in a non-infarct related artery. The secondary endpoints were IMR in the culprit artery and the fractional flow reserve (FFR) both in a non-infarct related artery and in the culprit artery. IMR measured in a non-infarct related artery was significantly lower after 72 h of ticagrelor treatment (19.2 ± 11.2 vs. 14.2 ± 7.4, P = 0.02) whereas IMR in the culprit artery was not significantly different from baseline (13.1 ± 4.1 vs. 18.7 ± 11.4, P = 0.13). FFR measurements were not significantly different after ticagrelor treatment both in the non-infarct related artery and in the culprit artery after primary PCI (85 ± 0.15 vs. 0.86 ± 0.17, P = 0.80 and 0.98 ± 0.04 vs. 0.98 ± 0.04, P = 0.56 respectively) ( Table 1 ). Ticagrelor decreases microvascular resistance in non-infarct related artery in ASC patients with MVD.

15 A clinical decision tool for prescribing anti-platelet medication for patients with suspected acute coronary syndrome (PAM)

BackgroundThe benefit of antiplatelet medication in confirmed acute coronary syndrome (ACS) is well established. In the Emergency Department (ED) diagnostic uncertainty may lead to over-treatment, with consequent risks (e.g., bleeding),...

Risk scoring to guide antiplatelet therapy post-percutaneous coronary intervention for acute coronary syndrome results in improved clinical outcomes.

To use the Global Registry of Acute Coronary Events (GRACE) and Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) scores to risk stratify antiplatelet treatment post-acute coronary syndrome (ACS). This was a prospective registry of 3374 patients undergoing percutaneous coronary intervention for ACS between 2013 and 2015 at a UK cardiac centre. Patients with either low GRACE or high CRUSADE risk scores were stratified either to clopidogrel therapy or ticagrelor was used. The primary endpoint was major adverse cardiac events (MACE) defined as death, non-fatal myocardial infarction, stroke, or target vessel revascularization with bleeding rates as a secondary outcome, assessed at a median follow-up of 1.8 years (interquartile range 0.8-3.4 years). A total of 1723 (51.1%) patients were risk stratified to either clopidogrel (n = 520) or ticagrelor treatment (n = 1203), with the remaining 1651 not risk scored and treated with clopidogrel therapy. Patients in the risk score stratified group were older than the control group otherwise the groups were similar. Over the follow-up period, a significant reduction in MACE rates between the patients' risk score stratified and control (clopidogrel therapy) (13.7% vs. 19.7%, P < 0.0001) was seen [hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.31-0.86]. This persisted after adjusting for baseline variables (HR 0.65, 95% CI 0.37-0.89) and propensity matching (HR = 0.63, 95% CI 0.27-0.93; P = 0.0015) No significant differences in the rate of major bleeding were seen between the groups (5.3% vs. 5.1%, P = 0.86). In the risk-stratified group, no difference in outcome (ischaemic/bleeding) was seen between clopidogrel and ticagrelor. Our registry data suggest that using appropriate risk scoring to guide antiplatelet therapy after ACS is safe and can result in improved clinical outcomes.

Anti-platelet effects of epigallocatechin-3-gallate in addition to the concomitant aspirin, clopidogrel or ticagrelor treatment.

Background/AimsAlthough epigallocatechin-3-gallate (EGCG), which is found in high contents in the dried leaves of green tea, has been reported to have an anti-platelet effect, synergistic effects of EGCG in addition to current anti-platelet medications remains to be elucidated.MethodsBlood samples were obtained from 40 participants who took aspirin (ASA, n = 10), clopidogrel (CPD, n = 10), ticagrelor (TCG, n = 10) and no anti-platelet medication (Control, n = 10). Ex vivo platelet aggregation and adhesion under various stimulators were analyzed by multiple electrode aggregometry (MEA) and Impact-R systems. PAC-1 and P-selectin expressions in human platelets were analyzed by flow cytometry.ResultsIn MEA analysis, adenosine diphosphate (ADP) and thrombin receptor activating peptide (TRAP)-induced platelet aggregations were lower in the CPD and the TCG groups; arachidonic acid (AA)-induced platelet aggregation was lower in the ASA group, whereas collagen (COL)-induced platelet aggregations were comparable among four groups. EGCG significantly reduced ADP- and COL-induced platelet aggregation in dose-dependent manner (ADP, p = 0.04; COL, p < 0.01). There were no additional suppressions of platelet aggregation stimulated by AA in the ASA group, and by ADP in the CPD and TCG groups. Moreover, EGCG suppressed shear stress-induced platelet adhesion on Impact-R, and had no effect on P-selectin and PAC-1 expressions.ConclusionsEx vivo treatment of EGCG inhibited platelet adhesion and aggregation without changes in P-selectin and PAC-1 expression. There was no additional suppressions in platelet aggregation stimulated by AA in the ASA group and ADP in the CPD and TCG groups.

Thrombus aspiration and prehospital ticagrelor administration in ST-elevation myocardial infarction: Findings from the ATLANTIC trial

The potential interactions between prehospital (pre-H) ticagrelor administration and thrombus aspiration (TA) in patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) have never been studied. Therefore, we evaluated the potential benefit of TA and pre-H ticagrelor treatment in patients enrolled in the ATLANTIC trial (NCT01347580). This analysis included 1,630 patients who underwent primary PCI. Multivariate analysis was used to explore the potential association of TA and pre-H treatment to clinical outcomes. Potential interactions between TA and pre-H ticagrelor were also explored. A total of 941 (57.7%) patients underwent TA. In adjusted multivariate logistic model, pre-H ticagrelor treatment was significantly associated with less frequent new MI or definite stent *thrombosis (ST) (odds ratio [OR] 0.43, 95% CI 0.20-0.92, P=.031), or definite ST (OR 0.26, 95% CI 0.07-0.91, P=.036) at 30 days. Patients treated with TA had higher frequency of Thrombolysis in Myocardial Infarction (TIMI) flow 0-1 compared with no-TA group (80.7% vs 51.9%, P<.0001). TA when also adjusted for TIMI flow 0-1 showed significant association only for higher bailout use of glycoprotein IIb/IIIa inhibitors (OR 1.72, 95% CI 1.18-2.50, P=.004) and more frequent 30-day TIMI major bleeding (OR 2.92, 95% CI 1.10-7.76, P=.032). No significant interactions between TA and pre-H ticagrelor were present for the explored end points. TA when left to physicians' discretion was used in high-risk patients, was associated with bailout use of glycoprotein IIb/IIIa inhibitors and TIMI major bleeding, and had no impact on 30-day clinical outcomes. Conversely, pre-H ticagrelor treatment predicted lower 30-day rates of ST or new MI without interaction with TA.