Ticagrelor Loading Dose Research Articles

Ticagrelor versus clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction: Rationale and design of the ticagrelor in patients with ST elevation myocardial infarction treated with thrombolysis (TREAT) trial

BackgroundThe safety and efficacy of ticagrelor in patients with ST-elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remain uncertain. ObjectivesThe primary objective of the TicagRElor in pAtients with ST elevation myocardial infarction treated with Thrombolysis (TREAT) trial is to evaluate the short-term safety of ticagrelor when compared with clopidogrel in STEMI patients treated with fibrinolytic therapy. Key secondary objectives are to assess the safety and efficacy of ticagrelor compared with clopidogrel at 12-months. DesignThe TREAT trial is a multicenter, randomized, phase III, Prospective randomized open blinded end-point (PROBE) study that enrolled 3,799 patients in 152 sites from 10 countries. Following administration of fibrinolytic therapy patients were randomized to a loading dose of ticagrelor 180 mg or clopidogrel 300 mg followed by a maintenance dose of ticagrelor 90 mg twice daily or clopidogrel 75 mg/day for 12-months. The primary outcome is the rate of TIMI major bleeding at 30-days and will be assessed for non-inferiority using an intention-to-treat analysis. Co-treatments include aspirin and anticoagulants. Other evidence based therapies are also recommended. Secondary efficacy outcome include a composite of death from vascular causes, myocardial infarction, stroke, severe recurrent ischemia, transient ischemic attack or other arterial thrombotic event. All-cause mortality as well as individual components of the combined efficacy endpoint will also be ascertained. SummaryTREAT is an international randomized controlled trial comparing ticagrelor with clopidogrel in STEMI patients treated with fibrinolytic therapy. The results of this trial will inform clinical practice and international guidelines.

Antithrombotic efficacy of bivalirudin compared to unfractionated heparin during percutaneous coronary intervention for acute coronary syndrome

Bivalirudin is associated with an increased risk of acute stent thrombosis (AST) compared to unfractionated heparin (UFH) in acute coronary syndrome patients (ACS) during short-duration percutaneous coronary intervention (PCI). The mechanisms involved are unknown. We aimed to investigate the antithrombotic efficacy of bivalirudin compared to UFH during PCI. In a monocenter study, we prospectively enrolled 30 patients undergoing PCI for a non–ST elevation ACS. They were randomly assigned to a single intravenous (IV) bolus of UFH (70 IU/kg) or an IV bolus of bivalirudin 0.75 mg/kg followed by a 1.75 mg/kg/h infusion during PCI. All patients received a loading dose (LD) of 180 mg of ticagrelor at the time of PCI. The VASP index and activated partial thromboplastin time (aPTT) were used to assess the course of platelet reactivity (PR) and antithrombotic activity. The two groups were similar regarding baseline, angiographic, and interventional characteristics. There was no difference between the two groups in the course of PR following ticagrelor LD. An optimal PR inhibition was obtained 4 h after the LD of ticagrelor. The level of antithrombotic activity was significantly lower in the bivalirudin group compared to the UFH group (p < 0.001) during PCI but similar at 2 and 4 h post-PCI. We observed that, in ACS undergoing PCI, the antithrombotic efficacy of an IV bolus of bivalirudin is significantly lower than that of a 70-IU/kg UFH bolus. This could contribute to the excess in thrombotic acute events observed during short-duration PCI.

Antiplatelet Effect of Different Loading Doses of Ticagrelor in Patients With Non–ST-Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: The APELOT Trial

BackgroundWe hypothesized that a high ticagrelor loading dose (LD) may improve platelet inhibition in patients with non–ST-elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI). MethodsThis interventional multicentre open-label trial randomized 278 patients with NSTE-ACS to a high (360 mg) or conventional (180 mg) ticagrelor LD. The primary outcome was the platelet reactivity index (PRI) 1 hour after administration of the LD. Secondary outcomes included PRI at 0.5 hour, 1 hour, 8 hours, and 24 hours; periprocedural myocardial infarction (PMI); major cardiac adverse events; and bleeding events. ResultsTwo hundred sixty-two patients completed the major end points. PRI was lower in the high-LD group than in the conventional-LD group at any time point (all, P < 0.05), including at 1 hour (12.2% vs 16.7%; P = 0.023). At 0.5 hour, the high-LD group showed a lower high-platelet reactivity rate (49.6% vs 60.2%; P = 0.013) and a higher low-platelet reactivity rate (24.8% vs 12.8%; P = 0.017) than did the conventional LD group. No significant differences in the bleeding rates were found between the 2 groups (14% vs 14.3%). Four cases of PMI and 1 death in each group, as well as 1 acute myocardial infarction in the conventional LD group, occurred. There was no stroke, target lesion revascularization, or target vessel revascularization. ConclusionsDoubling the ticagrelor LD achieved faster onset and greater platelet inhibition without an increase in adverse events in patients with NSTE-ACS undergoing PCI.

Pre-hospital ticagrelor in ST-segment elevation myocardial infarction in the French ATLANTIC population

BackgroundATLANTIC was a randomized study comparing pre- and in-hospital treatment with a ticagrelor loading dose (LD) in ongoing ST-segment elevation myocardial infarction (STEMI). We sought to compare patient characteristics and clinical outcomes in France with other countries participating in ATLANTIC. MethodsThe population comprised 1862 patients, 660 (35.4%) from France and 1202 from 12 other countries. The main endpoints were reperfusion (≥70% ST-segment elevation resolution) and TIMI flow grade 3 before (co-primary endpoints) and after percutaneous coronary intervention (PCI). Other endpoints included a composite ischaemic endpoint (death/myocardial infarction/stroke/urgent revascularization/definite stent thrombosis) and bleeding events at 30days. ResultsIn France, median times from first LD to angiography and between first and second LDs were 49 and 35min, respectively, and were similar to other countries. French patients were younger (mean 58.7 vs 61.9years, p<0.0001) and characterized by a higher rate of radial access (89.9% vs 54.8%, p<0.0001), more frequent use of pre-hospital glycoprotein (GP) IIb/IIIa inhibitors (14.1% vs 3.1%, p<0.0001) and intravenous enoxaparin (57.3% vs 10.1%, p<0.0001). In France, as in other countries, the co-primary endpoints did not differ between the two randomization groups. The composite ischaemic endpoint was numerically lower in France (3.3% vs 5.1%, p=0.07), with a lower mortality (1.4% vs 3.3%, p=0.01). PLATO major bleeding was numerically less frequent in France (1.8% vs 3.2%, p=0.07). ConclusionsThe French population appears to have better outcomes than the rest of the study population, and seems related to differences in demographics and management characteristics. Trial registryClinicalTrials.gov (NCT01347580).

Efficacy and safety of preoperative Ticagrelor loading treatment in emergency percutaneous coronary intervention for acute ST-segment elevation myocardial infarction

Objective To observe the safety and efficacy of preoperative Ticagrelor loading in emergency percutaneous coronary intervention(PCI)for acute ST-segment elevation myocardial infarction(STEMI). Methods A total of 213 patients with acute STEMI before undergoing emergency PCI were randomly divided into Ticagrelor group(n=105)receiving 180 mg Ticagrelor loading dose, then 90 mg twice daily and Clopidogrel group(n=108) receiving 600 mg of Clopidogrel, then 75 mg once daily.Emergency PCI postoperative coronary artery TIMI flow grade and the change of incidence of no reflow, platelet aggregation rate, incidence of bleeding events and the incidence of major adverse cardiovascular events(MACE)were compared between two groups. Results The rate of no-reflow was 7.6%(8 cases)in Ticagrelor group, and 16.7%(18 cases)in Clopidogrel group(χ2=3.26、P=0.030). Platelet aggregation rates at 1 h and 24 h after treatment were (55.6±4.3)% and(48.6±4.1)% respectively in Ticagrelor group, and (63.6±3.8)% and(57.6±3.6)% respectively in Clopidogrel group, which showed that platelet aggregation inhibition effect was better in Ticagrelor than in Clopidogrel(t=14.40、17.20, both P=0.001). Two groups had no major life-threatening bleeding events.Bleeding incidence had no statistically significant difference between two groups(χ2=0.14, P=0.710), and the incidence of cardiovascular adverse events showed no statistically significant difference(χ2=0.04, P=0.840)between the 2 groups. Conclusions Preoperativeticagrelor loading treatment in emergency PCI therapy for acute ST segment elevation myocardial infarction shows stronger antiplatelet aggregation function, significantly improve postoperative TIMI flow, and does not increase the incidence of bleeding events. Key words: Myocardial infarction; Angioplasty, transluminal, percutaneous coronary

Comparison of Ticagrelor Pharmacokinetics and Pharmacodynamics in STEMI and NSTEMI Patients (PINPOINT): protocol for a prospective, observational, single-centre study

IntroductionThe most common classification of acute myocardial infarction (AMI) is based on electrocardiographic findings and distinguishes ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI). Both types of AMI differ...

Effect of a 180 mg ticagrelor loading dose on myocardial necrosis in patients undergoing elective percutaneous coronary intervention: A preliminary study.

To examine whether a loading dose of ticagrelor on top of clopidogrel reduced postpercutaneous coronary intervention (PCI) myonecrosis. Seventy seven coronary artery disease patients received a loading dose of 300 mg clopidogrel pre-PCI and were divided into three groups: group TT (n = 36): a loading dose of 180 mg ticagrelor pre-PCI, followed by ticagrelor 90 mg twice daily commencing one day post-PCI; group CT (n = 26): a maintenance dose of ticagrelor 90 mg twice daily; group CC (n = 15): clopidogrel 75 mg daily post- PCI. High sensitivity cardiac troponin T (hs-cTnT) and creatine kinase-MB (CK-MB) were measured pre-PCI and 0 h, 2 h or 24 h post-PCI. Platelet aggregation was measured in a separate cohort of 54 coronary artery disease patients (35 diabetic and 19 non-diabetic patients). There were no significant differences in hs-cTnT and CK-MB concentration among the three groups. In group TT, diabetic patients had significant higher Δhs-cTnT2h-0h than non-diabetic patients. In the second cohort, although baseline platelet aggregation was higher in diabetic than non-diabetic patients, platelet aggregation was comparable between diabetic and non-diabetic patients at 0 and 2 h post-PCI. This study indicates that a loading dose of ticagrelor does not significantly reduce post- PCI myonecrosis. Diabetes is associated with more post-PCI myonecrosis. A loading dose of ticagrelor effectively reduces platelet aggregation in diabetic patients.

Ticagrelor pharmacokinetics and pharmacodynamics in patients with NSTEMI after a 180-mg loading dose

The pharmacokinetics after a 180-mg loading dose (LD) of ticagrelor has not been thoroughly investigated in NSTEMI patients. We aimed to compare the ticagrelor uptake and on-treatment platelet reactivity between non-ST-segment elevation myocardial infarction (NSTEMI) patients and a control group of patients with stable coronary artery disease (SCAD) undergoing elective percutaneous coronary intervention. We performed an observational, prospective, single-center study including 40 NSTEMI patients and 20 SCAD controls. Key exclusion criteria included ongoing opioid treatment. Both groups received a 180-mg ticagrelor LD, and blood samples were taken pre-dose and 1, 2, 3, 4, 5, and 6 hours post-LD. Plasma concentrations of ticagrelor and its active metabolite AR-C124910XX were determined by validated methods. Platelet aggregation was tested using ADP-induced multiple electrode aggregometry. The primary endpoint was the time to maximal ticagrelor concentration (Tmax). Clinical trial registration identifier number: NCT02292277. None of the pharmacokinetic variables differed significantly between the groups, including the Tmax of ticagrelor (2.0h [1.0–3.0] versus 2.0h [2.0–3.0], p = 0.393) and the active metabolite AR-C124910XX (3.0 [2.0–4.0] versus 3.0 [2.5–4.0], p = 0.289). High on-treatment platelet reactivity (HPR) was defined as > 46 aggregation units and was at one hour seen in 15% of the NSTEMI patients versus 10% of the controls (p = 1.0). At two hours post the 180-mg ticagrelor LD, 3% of the NSTEMI patients had HPR compared with none of the controls (p = 1.0). In conclusion, the uptake of ticagrelor was not significantly slower in NSTEMI patients not receiving opioids compared with the SCAD controls, leading to adequate onset of platelet inhibition in both groups.

The effect of TIcagrelor administered through a nasogastric tube to COMAtose patients undergoing acute percutaneous coronary intervention: the TICOMA study.

Patients in a coma after cardiac arrest may have adversely affected drug absorption and metabolism. This study, the first of its kind, aimed to investigate the early pharmacokinetic and pharmacodynamic effects of ticagrelor administered through a nasogastric tube (NGT) to patients resuscitated after an out of hospital cardiac arrest (OHCA) and undergoing primary percutaneous coronary intervention (pPCI). Blood samples were drawn at baseline and at two, four, six, eight, 12, and 24 hours and then daily for up to five days after administration of a 180 mg ticagrelor loading dose (LD), followed by 90 mg twice daily in 44 patients. The primary endpoint was the occurrence of high platelet reactivity (HPR) 12 hours after the LD. Assessment by VerifyNow (VFN) showed 96 (15.25-140.5) platelet reactivity units (PRU), and five (12%) patients exhibited HPR. Multiplate analysis showed 19 (12-29) units (U) at twelve hours, and three patients (7%) had HPR. Ticagrelor and its main metabolite AR-C124910XX concentrations were 85.2 (37.2-178.5) and 18.3 (6.4-52.4) ng/mL. Median times to sufficient platelet inhibition below the HPR limit were 3 (2-6) hours (VFN) and 4 (2-8) hours (Multiplate). Ticagrelor, administered as crushed tablets through a nasogastric tube, leads to sufficient platelet inhibition after 12 hours, and in many cases earlier, in the vast majority of patients undergoing pPCI and subsequent intensive care management after an OHCA.

Comparison of Platelet Reactivity in Black Versus White Patients With Acute Coronary Syndromes After Treatment With Ticagrelor

Ticagrelor, a potent platelet inhibitor, has primarily been studied in white patients. Platelet reactivity among black patients with acute coronary syndrome (ACS) on ticagrelor, however, is unknown. Our objective was to compare platelet reactivity in black versus white patients with ACS treated with ticagrelor. We conducted a prospective, pharmacodynamic study of 29 black patients with ACS treated with ticagrelor. Platelet reactivity was assessed at 1, 4, and 8hours after a loading dose of ticagrelor 180mg and at 30days on a maintenance dose of ticagrelor 90mg twice daily. Assays included light transmission aggregometry, VerifyNow P2Y12, and vasodilator-stimulated phosphoprotein. We provided comparison with a historical white cohort. Platelet reactivity among blacks with ACS on ticagrelor was similar to that in whites, except that blacks had lower values at 4hours, 8hours, and on maintenance therapy for light transmission aggregometry with 20μmol/L adenosine diphosphate. Among blacks, high-on-treatment platelet reactivity for all 3 assays was uncommon at 1hour and nonexistent at 4hours, 8hours, and while on maintenance therapy. Blacks preloaded with clopidogrel (n= 17) had significantly lower results of VerifyNow (64 ± 65 vs 198 ± 86, p <0.001) and vasodilator-stimulated phosphoprotein (12.8 ± 21.6 vs 58.9 ± 19.9, p <0.001) at 1hour compared with those with no clopidogrel preload. In conclusion, among patients with ACS receiving ticagrelor, levels of platelet reactivity in blacks are similar to that in whites. This suggests that the cardiovascular benefits of ticagrelor observed in the platelet inhibition and patient outcomes (PLATO) trial are likely to be observed in blacks and whites.

Validation of a New ELISA-Based Vasodilator-Associated Stimulated Phosphoprotein Phosphorylation Assay to Assess Platelet Reactivity Index in a Chinese Population.

The level of platelet reactivity during P2Y12-adenosine diphosphate receptor antagonist is associated with ischemic and bleeding risks following percutaneous coronary intervention in acute coronary syndrome. Determining platelet reactivity inhibition may be valuable for confirming effective platelet inhibition for individual patients and identifying patients at risk of bleeding. The enzyme-linked immunosorbent assay (ELISA)-based vasodilator-stimulated phosphoprotein (VASP) assay offers unique advantages over other methods and has not been used in the Chinese population. We enrolled 10 healthy volunteers and 54 patients with acute coronary syndrome. The volunteers received no treatment, and patients were administered a loading dose of clopidogrel or ticagrelor. The platelet reactivity index (PRI) was measured using flow cytometry (FC)-VASP and ELISA-VASP at baseline and 8-hour postloading dose. Blood samples of healthy volunteers and clopidogrel- or ticagrelor-treated patients were frozen and stored for 1, 2, and 4 weeks after initial activation. All frozen samples were tested using ELISA-VASP. The PRI assessed by FC-VASP and ELISA-VASP correlated well showing a high degree of consistency in identifying high or low on-treatment platelet reactivity. No significant time-dependent changes in PRI results were observed in frozen samples stored up to 4 weeks compared to nonfrozen samples. The PRI of ticagrelor-treated patients was lower than that of clopidogrel-treated patients. The ELISA-VASP effectively assesses the PRI, and results obtained from frozen specimens are unaffected by storage and shipment prior to assay. Ticagrelor was superior to clopidogrel in decreasing the PRI.

No Effect of &lt;i&gt;SLCO1B1&lt;/i&gt; and &lt;i&gt;CYP3A4/5&lt;/i&gt; Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Male Subjects

Ticagrelor is a direct-acting P2Y12 receptor antagonist. It is rapidly absorbed and partly metabolized to the active metabolite AR-C124910XX by CYP3A4 and CYP3A5. Three genetic loci (SLCO1B1, CYP3A4, and UGT2B7) were reported to affect ticagrelor pharmacokinetics. This study aimed to investigate the possible effects of SLCO1B1 and CYP3A4/5 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese male volunteers. Eighteen healthy male volunteers who participated in pharmacogenetics study of ticagrelor were genotyped for SLCO1B1 rs113681054, SLCO1B1*5 (rs4149056), CYP3A4*1G (rs2242480), and CYP3A5*3 (rs776746). All subjects received a single 180 mg loading dose of ticagrelor and then series blood samples were collected from 0 to 48 h. Plasma concentrations of ticagrelor and AR-C124910XX were determined by the high performance liquid chromatography-tandem mass spectrometry method. Inhibition in platelet aggregation (IPA) was assessed and the area under the time-effect curve (AUEC) for the IPA was calculated as pharmacodynamic parameters. No significant difference in ticagrelor pharmacokinetics among genotypes of the two genes was observed. The AUEC did not differ significantly among genotypes of candidate single nucleotide polymorphisms (SNPs). Our data suggest that common genetic variants in SLCO1B1 and CYP3A4/5 may have no effect on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese volunteers.

The influence of metoclopramide on pharmacokinetics and pharmacodynamics of ticagrelor in patients with unstable angina pectoris receiving concomitant treatment with morphine — a protocol of a randomized trial

Introduction. Nowadays, due to the “morphine effect”, the screening of methods that provide quick and effective platelet inhibition with oral P2Y12 inhibitors administrated simultaneously with morphine in patients with acute coronary syndromes are extensively investigated by numerous scientists. Metoclopramide, which stimulates the motility of gastrointestinal tract, may become a potential method of overcoming the negative morphine effect. The present study was designed to demonstrate the influence of metoclopramide administration on the pharmacokinetic and pharmacodynamic profile of ticagrelor between patients with unstable angina pectoris treated with morphine and crushed ticagrelor. Methods/design. A study was designed as a phase IV, single-centre, randomized, investigator-initiated, parallel-group, open-label, interventional trial. Patients will be randomized in a 1:1 manner into two arms: 1) patients treated with a combination of crushed ticagrelor and morphine and 2) patients treated with a combination of crushed ticagrelor followed by morphine and metoclopramide. Blood sample collection will be scheduled directly before the administration of ticagrelor loading dose and 15, 30, 45, 60, 120, 180, 240, and 360 minutes after the loading dose. Pharmacokinetic and pharmacodynamic assessment of ticagrelor and its active metabolite will be evaluated in all pre-defined time points. Discussion. The current study is, to our knowledge, the first one to provide data on the influence of metoclopramide in patients with acute coronary syndromes, who received intravenous opioid analgesia. It is expected to contribute to the development of contemporary knowledge on the treatment of patients presenting with acute coronary syndromes, and should enable clinicians to implement strategies of quick platelet inhibition.

Abstract 13849: Enhancing Anti-thrombotic Efficacy but Reducing Hemorrhage: Comparison and Combination Use of a Novel Integrin Outside-in Signaling Inhibitor With Current Anti-platelet Drugs

Introduction and Hypothesis: Current anti-platelets drugs cause excessive bleeding. We have developed a novel anti-platelet drug, M3mP6, which selectively inhibits integrin outside-in signaling but not ligand binding to integrin αIIbβ3. Here we test the hypothesis that M3mP6 may synergistically enhance anti-thrombotic effects of current anti-platelet drugs but reduce risk of hemorrhage. Methods and Results: One time bolus injection of M3mP6 (10 uMol/kg,15 min) has superior anti-thrombotic effect compared to high doses of clopidogrel (4 mg/kg, oral, 2 hours), and very high doses of aspirin (36 mg/kg, i.p., 1 hour), using a FeCl 3 -induced occlusive carotid artery thrombosis model in mice. However, unlike the high doses of clopidogrel and aspirin, M3mP6 did not affect bleeding using a tail bleeding time model. We found that M3mP6 was comparable with the loading doses of ticagrelor (3 mg/kg) and cangrelor (30 μg/kg) in anti-thrombotic efficacy. However, ticagrelor or cangrelor cause dramatically increased hemorrhage, which is in contrast to M3mP6’s lack of bleeding side effect. To mimic hemorrhage during intravascular/surgical procedures, we designed a carotid artery puncture model of surgical hemorrhage. Cangrelor caused dramatically excessive bleeding even treated with a hemostatic pad. In contrast, M3mP6-treated mice are not different from control. Importantly, M3mP6 exerts synergistic anti-thrombotic effects when used together with current anti-platelets drugs, without further increases in bleeding. Furthermore, when M3mP6 was used in combination with a reduced dose of cangrelor, the anti-thrombotic effect was significantly more potent than high dose cangrelor, but hemorrhage was greatly reduced. Conclusions: M3mP6 is potentially a superior new anti-platelet drug, ideal for patients with bleeding risk, and also for greatly enhancing anti-thrombotic effects of current anti-platelet drugs while reducing hemorrhage.

Abstract 12079: Initial Report From an Emergency-Department-Based Registry of NSTEMI Patients Given Upstream Advanced Oral Antiplatelet Therapy

Introduction: There are scant data on use of P2Y12 antagonist therapy upstream of diagnostic angiography (DA), especially when administered in the emergency department (ED) for NSTEMI. We are conducting a multicenter registry to describe patterns of upstream P2Y12 antagonist use and outcomes. Methods: UPSTREAM (NCT02271022) is an ongoing US multicenter, prospective, non-interventional registry of consecutive NSTEMI patients, evaluated in an ED, who are given a loading dose (LD) of ticagrelor, clopidogrel, or prasugrel ≥4h prior to DA, with DA performed ≤72h after ED arrival. All patients are followed to hospital discharge. Patients receiving ticagrelor throughout the index hospitalization and at discharge are also followed for vital status, rehospitalization, bleeding complications, and P2Y12 compliance at 30 days post-discharge. Results: We report in-hospital outcomes of the first 578 patients to have data entry completed at 24 US hospitals. Upstream P2Y12 LD was clopidogrel in 60%, ticagrelor in 39%, and prasugrel in 1%. Of these, 234 (40%) received at least one dose of ticagrelor; 116 (20.1%) were ticagrelor-consistent and had follow-up completed. One-fifth of patients were transferred to an UPSTREAM hospital. Mean age was of the poverall sample was 63 years with 19% older than 75. Approximately 23% of patients had a documented prior MI, 31% had at least one prior stent, and 16% had prior CABG. Chest pain was not part of presenting symptoms in 15%. The median (+/-IQR) time from first ED arrival to LD was 6.7h (+/- 6.8 h); time from LD to DA was 12h (+/- 9.6 h). DA was performed via femoral access in 66% of patients and radially in 34%. Post-DA management was 55% stent, 9% CABG, and 35% medical management. In-hospital CV events (0.7%), including mortality, were infrequent. Only 14 patients (6 [1.0%] CABG-related and 8 non-CABG patients [1.4%]) required RBC transfusion, while 8 (6 CABG-related) required a platelet transfusion. One stent thrombosis event was recorded. Conclusions: Upstream P2Y12 therapy in NSTEMI patients undergoing an invasive strategy is associated with good clinical outcomes and minimal risk of bleeding complications. The most commonly used upstream P2Y12 LD was clopidogrel, but in-hospital switching was common. Updated data will be shown.

Rationale and Design of ST-ON-SET: Assessment of Antiplatelet Effect after Ticagrelor Loading Dose in STEMI pPatients and NSTEMI Patients

&lt;p&gt;Background: Delayed platelet inhibition by ticagrelor has been initially documented in STEMI subjects. To the best of our knowledge, no data exists about the direct description of early onset of platelet inhibition after ticagrelor loading dose (LD) in different clinical forms of ACS, especially in Chinese patients. The ST-ON-SET study is designed to address this unmet need.&lt;/p&gt;&lt;p&gt;&lt;br /&gt; Method/Design: The ST-ON-SET study is a single center, prospective, observational, open-label, investigator-initiated study. Platelet inhibition assessed by Light transmittance aggregometry (LTA) and plasma concentrations of ticagrelor and its metabolites would be investigated serially. The primary outcome is the inhibition of platelet aggregation measured by LTA at 2 hours after ticagrelor LD. Moreover, baseline inflammatory and thrombotic biomarkers would be measured to investigate the potential underlying influences of platelet inhibition.&lt;/p&gt;Conclusion: The study is designed to characterize pharmacokinetic and pharmacodynatic profiles of ticagrelor LD in Chinese STEMI and NSTEMI patients. Furthermore, preliminary investigation of the underlying mechanism of initial delayed platelet inhibition by ticagrelor would be conducted.

Protective Effects of Ticagrelor on Myocardial Injury After Infarction.

The P2Y12 receptor antagonist ticagrelor has been shown to be clinically superior to clopidogrel. Although the underlying mechanisms remain elusive, ticagrelor may exert off-target effects through adenosine-related mechanisms. We aimed to investigate whether ticagrelor reduces myocardial injury to a greater extent than clopidogrel after myocardial infarction (MI) at a similar level of platelet inhibition and to determine the underlying mechanisms. Pigs received the following before MI induction: (1) placebo-control; (2) a loading dose of clopidogrel (600 mg); (3) a loading dose of ticagrelor (180 mg); or (4) a loading dose of ticagrelor followed by an adenosine A1/A2-receptor antagonist [8-(p-sulfophenyl)theophylline, 4 mg/kg intravenous] to determine the potential contribution of adenosine in ticagrelor-related cardioprotection. Animals received the corresponding maintenance doses of the antiplatelet agents during the following 24 hours and underwent 3T-cardiac MRI analysis. Platelet inhibition was monitored by ADP-induced platelet aggregation. In the myocardium, we assessed the expression and activation of proteins known to modulate edema formation, including aquaporin-4 and AMP-activated protein kinase and its downstream effectors CD36 and endothelial nitric oxide synthase and cyclooxygenase-2 activity. Clopidogrel and ticagrelor exerted a high and consistent antiplatelet effect (68.2% and 62.2% of platelet inhibition, respectively, on challenge with 20 μmol/L ADP) that persisted up to 24 hours post-MI (P<0.05). All groups showed comparable myocardial area-at-risk and cardiac worsening after MI induction. 3T-Cardiac MRI analysis revealed that clopidogrel- and ticagrelor-treated animals had a significantly smaller extent of MI than placebo-control animals (15.7 g left ventricle and 12.0 g left ventricle versus 22.8 g left ventricle, respectively). Yet, ticagrelor reduced infarct size to a significantly greater extent than clopidogrel (further 23.5% reduction; P=0.0026), an effect supported by troponin-I assessment and histopathologic analysis (P=0.0021). Furthermore, in comparison with clopidogrel, ticagrelor significantly diminished myocardial edema by 24.5% (P=0.004), which correlated with infarct mass (r=0.73; P<0.001). 8-(p-Sulfophenyl)theophylline administration abolished the cardioprotective effects of ticagrelor over clopidogrel. At a molecular level, aquaporin-4 expression decreased and the expression and activation of AMP-activated protein kinase signaling and cyclooxygenase-2 increased in the ischemic myocardium of ticagrelor- versus clopidogrel-treated animals (P<0.05). These protein changes were not observed in those animals administered the adenosine receptor blocker 8-(p-sulfophenyl)theophylline. Ticagrelor, beyond its antiplatelet efficacy, exerts cardioprotective effects by reducing necrotic injury and edema formation via adenosine-dependent mechanisms.

Chewed ticagrelor tablets provide faster platelet inhibition compared to integral tablets: The inhibition of platelet aggregation after administration of three different ticagrelor formulations (IPAAD-Tica) study, a randomised controlled trial

AimsTo provide pharmacodynamic data of crushed and chewed ticagrelor tablets, in comparison with standard integral tablets. MethodsNinety nine patients with stable angina were randomly assigned, in a 3:1:1 fashion, to one of the following 180mg ticagrelor loading dose (LD) formulations: A) Integral B) Crushed or C) Chewed tablets. Platelet reactivity (PR) was assessed with VerifyNow before, 20 and 60min after LD. High residual platelet reactivity (HRPR) was defined as >208 P2Y12 reaction units (PRU). ResultsThere was no significant difference in PRU values at baseline. PRU 20min after LD were 237 (182–295), 112 (53–238) and 84 (29–129) and 60min after LD, 56 (15–150), 51 (18–85) and 9 (7–34) in integral, crushed and chewed ticagrelor LD, respectively (p<0.01 for both). Chewed ticagrelor tablets resulted in significantly lower PRU values compared to crushed or integral tablets at 20 and 60min. Crushed ticagrelor LD resulted in significantly lower PRU values compared to integral tablets at 20min whereas no difference was observed at 60min.At 20min, no patients had HRPR with chewed ticagrelor compared to 68% with integral and 30% with crushed ticagrelor LD (p<0.01). ConclusionWith crushed or chewed ticagrelor tablets a more rapid platelet inhibition may be achieved, compared to standard integral tablets. We also show that administration of chewed tablets is feasible and provides faster inhibition than either crushed or integral tablets.CLINICAL TRIAL REGISTRATION: European Clinical Trial Database (EudraCT number 2014-002227-96).

GW27-e0058 Comparisons of loading doses of ticagrelor versus clopidogrel in preventing periprocedural myocardial infarction

GW27-e0058 Comparisons of loading doses of ticagrelor versus clopidogrel in preventing periprocedural myocardial infarction

Periprocedural platelet inhibition with cangrelor in P2Y12-inhibitor naïve patients with acute coronary syndromes — A matched-control pharmacodynamic comparison in real-world patients

BackgroundEffective inhibition of platelet aggregation during PCI in high risk patients with ACS is of utmost importance. The new intravenous short acting P2Y12-receptor inhibitor cangrelor is available for use in PCI-treated patients. We aimed to study platelet inhibition during treatment with cangrelor and transition phase with oral P2Y12-receptor inhibitors in patients with acute coronary syndromes (ACS). MethodsCangrelor was administered during PCI to 21 P2Y12-inhibitor naïve patients with ACS. Patients received a loading dose of ticagrelor at the time of procedure or prasugrel 30min before end of the cangrelor infusion. Platelet inhibition was measured by multiple electrode aggregometry (MEA) and thromboelastography (TEG), before and after PCI, immediately and 2h after stopping the infusion. Platelet inhibition after PCI was compared to a matched cohort of patients treated with oral P2Y12-inibitors only. ResultsThere was a significant reduction of platelet reactivity measured by MEA-ADP from 46.7U to 17.9U and by TEG MA ADP from 43.1mm to 22.0mm before infusion and after PCI respectively (p<0.001). There was also sustained platelet inhibition after stopping of cangrelor infusion and 2h later. Significant higher platelet inhibition was observed at the end of PCI in comparison to control cohort without cangrelor (MEA 17.9U vs. 54.2U, p=0.001). ConclusionWe demonstrate significantly improved platelet inhibition during PCI in ACS patients treated with cangrelor in comparison to early treatment with potent oral P2Y12-inhibitors. Cangrelor should be considered for periprocedural treatment of high risk patients with acute coronary syndrome.