Ticagrelor Treatment Research Articles

Ticagrelor versus clopidogrel for prevention of subclinical stent thrombosis detected by optical coherence tomography in patients with drug-eluting stent implantation—a multicenter and randomized study

Introduction: This prospective, multicenter, randomized study was designed to analyze the benefits of ticagrelor over clopidogrel in reducing subclinical stent thrombosis (ST) in patients with coronary artery disease who underwent implantation of a second-generation drug-eluting stent (DES). Methods: About 352 patients with single de novo coronary stenosis were randomly assigne`d to either clopidogrel group (aspirin plus clopidogrel) or ticagrelor group (aspirin plus ticagrelor) after DES implantation for 1 year. Baseline clinical characteristics, blood chemistry markers, coronary artery angiography (CAG), and optical coherence tomography (OCT) were obtained during the index procedure. Data about clinic, CAG and OCT were also collected after 1 year follow-up. Intention-to-treat (ITT), per protocol set (PPS), and sensitivity analysis of subclinical ST were performed. Major factors associated with subclinical ST were analyzed by multivariable and univariable logistic regression models. Results: The incidence of subclinical ST in ticagrelor group was significantly low as compared to clopidogrel group (P < .05) at 1-year follow-up. Ticagrelor use was an independent factor in reducing subclinical ST (P < .05). The percentage of endothelial coverage, neointimal hyperplasia, malapposition, and edge dissection about stents were not different between the two groups (P > .05). Bleeding ratio was not markedly altered after ticagrelor treatment (P > .05). Not any significant differences were detected with regard to baseline clinical characteristics, CAG results, and DES between ticagrelor and clopidogrel groups (P > .05). Conclusion: In patients who underwent a second-generation DES implantation, using aspirin plus ticagrelor was associated with a significant reduction in subclinical ST. (ClinicalTrials.gov. Number: NCT02140801)

Ticagrelor reverses the mitochondrial dysfunction through preventing accumulated autophagosomes-dependent apoptosis and ER stress in insulin-resistant H9c2 myocytes.

Ticagrelor, a P2Y12-receptor inhibitor, and a non-thienopyridine agent are used to treat diabetic patients via its effects on off-target mechanisms. However, the exact sub-cellular mechanisms by which ticagrelor exerts those effects remains to be elucidated. Accordingly, the present study aimed to examine whether ticagrelor influences directly the cardiomyocytes function under insulin resistance through affecting mitochondria-sarco(endo)plasmic reticulum (SER) cross-talk. Therefore, we analyzed the function and ultrastructure of mitochondria and SER in insulin resistance-mimicked (50-μM palmitic acid for 24-h) H9c2 cardiomyocytes in the presence or absence of ticagrelor (1-µM for 24-h). We found that ticagrelor treatment significantly prevented depolarization of mitochondrial membrane potential and increases in reactive oxygen species with a marked increase in the ATP level in insulin-resistant H9c2 cells. Ticagrelor treatment also reversed the increases in the resting level of free Ca2+ and mRNA level of P2Y12 receptors as well as preserved ER stress and apoptosis in insulin-resistant H9c2 cells. Furthermore, we determined marked repression with ticagrelor treatment in the increased number of autophagosomes and degeneration of mitochondrion, including swelling and loss of crista besides recoveries in enlargement and irregularity seen in SER in insulin-resistant H9c2 cells. Moreover, ticagrelor treatment could prevent the altered mRNA levels of Becklin-1 and type 1 equilibrative nucleoside transporter (ENT1), which are parallel to the preservation of ultrastructural ones. Our overall data demonstrated that ticagrelor can directly affect cardiomyocytes and provide marked protection against ER stress and dramatic induction of autophagosomes, and therefore, can alleviate the ER stress-induced oxidative stress increase and cell apoptosis during insulin resistance.

Real-World Dual Antiplatelet Therapy Following Polymer-Free Sirolimus-Eluting Stent Implantations to Treat Coronary Artery Disease

ObjectivesThe objective of this post hoc analysis was to analyze real-world dual antiplatelet therapy (DAPT) regimens following polymer-free sirolimus-eluting stent (PF-SES) implantations in an unselected patient population.MethodsPatient-level data from two all-comers observational studies (ClinicalTrials.gov Identifiers: NCT02629575 and NCT02905214) were pooled and analyzed in terms of their primary endpoint. During the data verification process, we observed substantial deviations from DAPT guideline recommendations. To illuminate this gap between clinical practice and guideline recommendations, we conducted a post hoc analysis of DAPT regimens and clinical event rates for which we defined the net adverse event rate (NACE) consisting of target lesion revascularization (TLR, primary endpoint of all-comers observational studies) all-cause death, myocardial infarction (MI), stent thrombosis (ST), and bleeding events. A logistic regression was utilized to determine predictors why ticagrelor was used in stable coronary artery disease (CAD) patients instead of the guideline-recommended clopidogrel.ResultsFor stable CAD, the composite endpoint of clinical, bleeding, and stent thrombosis, i.e., NACE, between the clopidogrel and ticagrelor treatment groups was not different (5.4% vs. 5.1%, p = 0.745). Likewise, in the acute coronary syndrome (ACS) cohort, the NACE rates were not different between both DAPT strategies (9.2% vs. 9.3%, p = 0.927). There were also no differences in the accumulated rates for TLR, myocardial infarction ([MI], mortality, bleeding events, and stent thrombosis in elective and ACS patients. The main predictors for ticagrelor use in stable CAD patients were age < 65 years, smaller vessels, treatment of ostial and calcified lesions, and in-stent restenosis.ConclusionWithin the framework of a post hoc analysis based on a real-world, large cohort study, there were no differences in the combined endpoint of major adverse cardiac events (MACE), bleeding and thrombotic events for clopidogrel and ticagrelor in stable CAD or ACS patients. Despite the recommendation for clopidogrel by the European Society of Cardiology (ESC), real-world ticagrelor use was observed in subgroups of stable CAD patients that ought to be explored in future trials.

The value of cytochrome P4502C19 gene assay for anti-platelet therapy after PCI in stable angina patients with left main coronary artery lesions

To evaluate the efficacy and safety of different antiplatelet therapies for stable angina patients with complicated left main coronary artery lesions and intermediate metabolizer Cytochrome P450 2C19 gene (CYP2C19) undergoing PCI. A total of 247 patients diagnosed with stable angina in cardiology department of Fujian union hospital from February 2015 to February 2017 were retrospectively analyzed, among them, the elective PCI were performed on the left main coronary artery and the CYP2C19 gene poly-morphism were intermediate metabolize, they were divided into ticagrelor treatment group(aspirin combined with ticagrelor, n=95)and clopidogrel treatment group(aspirin combined with clopidogrel, n=152) according to the different antiplatelet treatment programs. Both groups were given aspirin 300 mg and clopidogrel 300 mg orally before PCI; the ticagrelor group were given the maintenance dose of ticagrelor (90 mg orally, twice a day) after PCI, while those in clopidogrel group were clopidogrel 75 mg orally (once a day) after PCI; both groups were given the maintenance dose of aspirin (100 mg orally, once a day)after PCI. The major adverse cardiovascular events (MACE) were observed within 12 months after PCI. At 12 months after PCI, the incidence of MACE in the ticagrelor treatment group was significantly lower than that in the clopidogrel treatment group, the difference was statistically significant (2.1% vs 15.1%, P=0.001).There were no significant differences between the two groups in the restenosis rates of non- revascularized target vessel, recurrent rates of angina pectoris(but not myocardial infarction), recurrent rates of myocardial infarction, and revascularization rates of target vessel (P > 0.05). There were also no significant differences between the two groups in bleeding. For stable angina patients with complicated left main coronary artery lesions and intermediate metabolizer CYP2C19 gene, aspirin combined with ticagrelor antiplatelet therapy after PCI is effective, the effect of ticagrelor is better than clopidogrel on MACE, and ticagrelor does not seem to increase the risk of bleeding.

Investigate the Strategy of Using Pharmacogenetics and Pharmacometabonomics to the Personalization of Ticagrelor Antiplatelet Therapy

Background: Ticagrelor is an oral antiplatelet agent commonly used to inhibit P2Y12 receptors that bind to it inversely. It is classified as cyclopentyltriazolopyrimidine (CPTP). Unlike prasugrel and clopidogrel, ticagrelor does not require metabolism activation. Thus, in theory, it is less affected by the variability seen with CYP polymorphisms and thus produces a more stable antiplatelet effect. However, clinical and laboratory experiments showed some defects in the P2Y12 receptor antagonism of ticagrelor. Despite awareness of many genetic and non-genetic variables that pose challenges to personalising ticagrelor treatment, most of its variable platelet reactions remain unexplained. Pharmacometabonomics, a process of discovering new biomarkers of drug response or toxicity in biofluids, have been used to predict drug response. The strength of using the pharmacometabonomics technique is that it forecasts a response and offers extensive knowledge on the metabolic pathways of a response. Integrating pharmacogenetics with pharmacometabonomics provides insight into unknown response-related genetic and non-genetic factors. Method: The literature on the factors associated with the variable platelet reactivity of Ticagrelor was reviewed and the possible role of pharmacogenetics and pharmacometabonomics in the personalization of antiplatelet therapy with ticagrelor was discussed. Result: This review identified that pharmacometabonomic techniques are not presently used to predict the response to Ticagrelor. It also demonstrates that the use of pharmacogenetics alone to test the response to Ticagrelor has limitations. Conclusion: This study concluded that it is possible to use a combination of pharmacogenetics and pharmacometabonomics to predict the outcome of treatment with Ticagrelor. How to Cite this Article Pubmed Style Mohammed Ahmed Akkaif, Abubakar Shaaban, Nur Aizati Athirah Daud, Mei Li Ng, Baharudin Ibrahim. the Strategy of Using Pharmacogenetics and Pharmacometabonomics to the Personalization of Ticagrelor Antiplatelet Therapy. SRP. 2020; 11(9): 1100-1107. doi:10.31838/srp.2020.9.157 Web Style Mohammed Ahmed Akkaif, Abubakar Shaaban, Nur Aizati Athirah Daud, Mei Li Ng, Baharudin Ibrahim. the Strategy of Using Pharmacogenetics and Pharmacometabonomics to the Personalization of Ticagrelor Antiplatelet Therapy. http://www.sysrevpharm.org/?mno=44895 [Access: March 29, 2021]. doi:10.31838/srp.2020.9.157 AMA (American Medical Association) Style Mohammed Ahmed Akkaif, Abubakar Shaaban, Nur Aizati Athirah Daud, Mei Li Ng, Baharudin Ibrahim. the Strategy of Using Pharmacogenetics and Pharmacometabonomics to the Personalization of Ticagrelor Antiplatelet Therapy. SRP. 2020; 11(9): 1100-1107. doi:10.31838/srp.2020.9.157 Vancouver/ICMJE Style Mohammed Ahmed Akkaif, Abubakar Shaaban, Nur Aizati Athirah Daud, Mei Li Ng, Baharudin Ibrahim. the Strategy of Using Pharmacogenetics and Pharmacometabonomics to the Personalization of Ticagrelor Antiplatelet Therapy. SRP. (2020), [cited March 29, 2021]; 11(9): 1100-1107. doi:10.31838/srp.2020.9.157 Harvard Style Mohammed Ahmed Akkaif, Abubakar Shaaban, Nur Aizati Athirah Daud, Mei Li Ng, Baharudin Ibrahim (2020) the Strategy of Using Pharmacogenetics and Pharmacometabonomics to the Personalization of Ticagrelor Antiplatelet Therapy. SRP, 11 (9), 1100-1107. doi:10.31838/srp.2020.9.157 Turabian Style Mohammed Ahmed Akkaif, Abubakar Shaaban, Nur Aizati Athirah Daud, Mei Li Ng, Baharudin Ibrahim. 2020. the Strategy of Using Pharmacogenetics and Pharmacometabonomics to the Personalization of Ticagrelor Antiplatelet Reviews in Pharmacy, 11 (9), 1100-1107. doi:10.31838/srp.2020.9.157 Chicago Style Mohammed Ahmed Akkaif, Abubakar Shaaban, Nur Aizati Athirah Daud, Mei Li Ng, Baharudin Ibrahim. Investigate the Strategy of Using Pharmacogenetics and Pharmacometabonomics to the Personalization of Ticagrelor Antiplatelet Therapy. Systematic Reviews in Pharmacy 11 (2020), 1100-1107. doi:10.31838/srp.2020.9.157 MLA (The Modern Language Association) Style Mohammed Ahmed Akkaif, Abubakar Shaaban, Nur Aizati Athirah Daud, Mei Li Ng, Baharudin Ibrahim. Investigate the Strategy of Using Pharmacogenetics and Pharmacometabonomics to the Personalization of Ticagrelor Antiplatelet Therapy. Systematic Reviews in Pharmacy 11.9 (2020), 1100-1107. Print. doi:10.31838/srp.2020.9.157 APA (American Psychological Association) Style Mohammed Ahmed Akkaif, Abubakar Shaaban, Nur Aizati Athirah Daud, Mei Li Ng, Baharudin Ibrahim (2020) the Strategy of Using Pharmacogenetics and Pharmacometabonomics to the Personalization of Ticagrelor Antiplatelet Reviews in Pharmacy, 11 (9), 1100-1107. doi:10.31838/srp.2020.9.157

Beneficial Effects of Ticagrelor on Oxidized Low-Density Lipoprotein (ox-LDL)-Induced Apoptosis in Human Umbilical Vein Endothelial Cells.

BackgroundTicagrelor is the first oral anti-platelet agent which has direct anti-platelet aggregation effect by combining with ADP P2Y12 receptors in platelets. It has been approved to reduce the incidence of thrombus cardiovascular events in acute coronary syndrome patients. However, the effects of ticagrelor on endothelial apoptosis have not been investigated.Material/MethodsOxidized low-density lipoprotein (ox-LDL) was used to establish a human umbilical vein endothelial cell (HUVEC) apoptosis model. To investigate the effects of ticagrelor on endothelial apoptosis, the HUVECs were treated with different dose of ticagrelor. Apoptosis rates of HUVECs was evaluated by flow cytometry, and the expression levels of Akt, p-Akt, Bcl-2, Bax, caspase-3, endothelial nitric oxide synthase (eNOS), and nitric oxide (NO) concentration were assessed.ResultsAfter treatment with 50 ug/mL ox-LDL or 100 ug/mL ox-LDL, we found that the late apoptosis and necrosis rate and the expression levels of Bax and caspase-3 were significantly increased in HUVECs, whereas the expression levels of Akt, p-Akt, Bcl-2, eNOS, and NO were significantly decreased. Ticagrelor restored the apoptosis rate of ox-LDL-induced HUVECs in a dose-dependent manner. In addition, compared with ox-LDL group, ticagrelor treatment significantly increased the expression levels of Akt, p-Akt, Bcl-2, eNOS, and NO concentration, and significantly decreased the expression levels of Bax and caspase-3.ConclusionsWe found that ox-LDL induced significant apoptosis and necrosis in our model, which was dose-dependently improved by ticagrelor. These changes might be explained by alterations in apoptosis and antioxidant pathways.

Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health

BackgroundThe clinical efficacy of ticagrelor is questionable in East Asian populations. Patients with acute myocardial infarction (AMI) with multivessel disease (MVD) are considered as high risk patients who might benefit from ticagrelor treatment. The purpose of this study is to compare the clinical effect of ticagrelor and clopidogrel in AMI patients with MVD in Korea. Methods and resultsA total of 2275 patients between November 2011 and June 2015, diagnosed with AMI with MVD after successful percutaneous coronary intervention who were registered in the Korea Acute Myocardial Infarction Registry – National Institute of Health (KAMIR-NIH) were enrolled. Patients were divided into ticagrelor (n = 837) and clopidogrel group (n = 1438). The primary endpoint was major adverse cardiac events (MACE) defined as cardiac death, non-fatal MI, target vessel revascularization, or ischemic stroke during 2 years of clinical follow-up. Secondary endpoints were thrombolysis in myocardial infarction (TIMI) major or minor bleeding, net clinical event composed of MACE and TIMI major bleeding, any repeated percutaneous coronary intervention, heart failure requiring re-hospitalization, and stent thrombosis. After propensity score matching analysis, the primary endpoint was lower in ticagrelor group compared to the clopidogrel group (8.6 % vs. 11.9 %; HR: 0.68; 95 % CI: 0.50-0.94; p = 0.018). The risk of TIMI major or minor bleeding was higher in the ticagrelor group (10.8 % vs. 4.8 %; HR: 2.51; 95 % CI: 1.68–3.76; p < 0.001). The net clinical event was similar between ticagrelor and clopidogrel group (11.3 % vs. 13.6 %; HR 0.82; 95 % CI: 0.60–1.11; p = 0.195). ConclusionTicagrelor significantly reduced the risk of MACE than clopidogrel for AMI patients with MVD in Korea. However, the risk of TIMI major or minor bleeding was higher and the net clinical benefit was similar. Further large-scale multi-center randomized clinical trials are needed to clarify the proper use dual antiplatelet therapy in East Asian populations.

The Comparative Effects of Ticagrelor and Clopidogrel on Arterial Injury and In-Stent Restenosis and Thrombosis of Carotid Artery in Atherosclerotic Rabbits

Introduction - Carotid artery angioplasty and stenting (CAS) is expanding as a method to treat carotid artery disease worldwide. Until now a combination of aspirin and clopidogrel has been used pre and post CAS. Ticagrelor, a P2Y (12) inhibitor, has an important role in coronary artery angioplasty. There is lack of evidence about the impact of ticagrelor on carotid artery disease and CAS. Our aim was the comparative evaluation of ticagrelor and clopidogrel on carotid balloon-injury and in-stent restenosis (ISR) and thrombosis in rabbits. Methods - After a pharmacokinetic study to standardise the appropriate dose of ticagrelor, we enrolled 48 New Zealand White rabbits. They were fed a high-cholesterol diet for 8 weeks prior to and up to 4 weeks following interventions in the right carotid artery (RCA). Aspirin was administered orally (10mg/kg/day) to all rabbits, beginning 7 days before the procedures and continued until euthanasia (4 weeks later). At 8th week of age, all rabbits were randomly assigned into the following equivalent (N=12) groups: A1) Balloon injury and clopidogrel (30 mg/kg/day), A2) Balloon injury and ticagrelor (21mg/kg bd), B3) Balloon injury and CAS and clopidogrel (30 mg/kg/day), B4) Balloon injury and CAS and ticagrelor (21mg/kg bd). During CAS a balloon expandable 2,25x8 mm bare metal stent was implanted in the RCA. Before euthanasia optical coherence tomography (OCT) and angiography were carried out to evaluate the patency of both carotid arteries. Blood samples to measure platelet aggregation and lipid profile were obtainedas well. Rabbits were then immediately euthanized and both carotid arteries (right-RCA and left-LCA) were excised for histological analysis. Results - Among groups, no significant differences were seen regarding balloon injury, stent implantation success rates and platelet aggregation measurements (p>0.05). All groups had similar lipid levels (total cholesterol, triglycerides) and weight by the end of the study. Notably, 3 rabbits in the B3 group appeared with thrombotic total occlusion of the carotid stents and were excluded from morphometric analysis. None such episode was observed after CAS in ticagrelor-treated rabbits. In balloon injury rabbits, the OCT-calculated neointimal areas in RCAs were: A1: 4.20±0.96mm2, A2: 3.78±1.31mm2, p=0.781, while the mid-stent neointimal areas were: B1: 1.74±0.51mm2 and B2: 1.45±0.62mm2, p=0.654. The histological findings in balloon-injured rabbits were in agreement with those from OCT analysis, since the percentage of intima/(media + intima)(%) in RCA did not differ between groups: A1 (68.48±12.31%) vs A2 (64.22±13.22%) (p=0.812). Importantly the atherosclerotic lesions in non-injured LCAs did not differ between all groups (p>0.1). Conclusion - In atherosclerotic rabbits undergoing carotid artery balloon injury with or without stent implantation, clopidogrel and ticagrelor seemed to be equally effective in terms of neointimal formation and ISR prevention. . Importantly, ticagrelor treatment prevented thrombotic stent occlusions compared to clopidogrel treatment. Further studies are needed to clarify the impact of P2Y(12) inhibitors on carotid in-stent restenosis and thrombosis in humans.

Impaired adenylate cyclase signaling in acute myocardial ischemia: Impact on effectiveness of P2Y12 receptor antagonists

IntroductionP2Y12 receptor antagonists reduce risk of thrombotic complications after stent implantation but increase bleeding risk. Activation of P2Y12 receptors by ADP causes Gi-protein-mediated inhibition of adenylate cyclase (AC), thus limiting platelet response to anti-aggregatory effect of prostacyclin (PGI2). However, P2Y12 blockade reverses this ADP-induced suppression of the platelet PGI2/AC signaling pathway. We previously demonstrated that impairment of this pathway predicts poor response to clopidogrel. ObjectivesTo identify clinical correlates of variability in PGI2/AC signaling, and to assess the impact of such variability on individual responses to the direct P2Y12 receptor antagonists ticagrelor (in vivo) and 2-methyl-thioadenosine-monophosphate (2MeSAMP) (in vitro). Patients/MethodsWe compared the inhibitory effects of prostaglandin E1 (PGE1) and the PGI2 analog Iloprost (Ilt) on platelet aggregation in whole blood samples from healthy control subjects (n = 17), and patients with stable angina pectoris (SAP; n = 35) or acute coronary syndromes (ACS; n = 23), with or without associated diabetes/hyperglycemia. ResultsCompared to control subjects, patients with ACS and – to a lesser extent – those with SAP, exhibited impaired responses to PGE1, accentuated in the presence of hyperglycemia. Efficacy of ticagrelor treatment, measured as change in platelet reactivity index, was directly related to pre-treatment PGE1 response, both at univariate and multivariate analysis. There was a strong correlation between extent of inhibition of platelet aggregation, whether by PGE1 or Ilt, and the anti-aggregatory effect of 2MeSAMP in vitro. ConclusionsThe integrity of PGI2/AC signaling, which is impaired in the presence of ACS and hyperglycemia, predetermines the anti-aggregatory efficiency of P2Y12 receptor antagonists.

Oral Delivery of the P2Y12 Receptor Antagonist Ticagrelor Prevents Loss of Photoreceptors in an ABCA4-/- Mouse Model of Retinal Degeneration.

PurposeAccumulation of lysosomal waste is linked to neurodegeneration in multiple diseases, and pharmacologic enhancement of lysosomal activity is hypothesized to reduce pathology. An excessive accumulation of lysosomal-associated lipofuscin waste and an elevated lysosomal pH occur in retinal pigment epithelial cells of the ABCA4−/− mouse model of Stargardt's retinal degeneration. As treatment with the P2Y12 receptor antagonist ticagrelor was previously shown to lower lysosomal pH and lipofuscin-like autofluorescence in these cells, we asked whether oral delivery of ticagrelor also prevented photoreceptor loss.MethodsModerate light exposure was used to accelerate photoreceptor loss in albino ABCA4−/− mice as compared to BALB/c controls. Ticagrelor (0.1%–0.15%) was added to mouse chow for between 1 and 10 months. Photoreceptor function was determined with electroretinograms, while cell survival was determined using optical coherence tomography and histology.ResultsProtection by ticagrelor was demonstrated functionally by using the electroretinogram, as ticagrelor-treated ABCA4−/− mice had increased a- and b-waves compared to untreated mice. Mice receiving ticagrelor treatment had a thicker outer nuclear layer, as measured with both optical coherence tomography and histologic sections. Ticagrelor decreased expression of LAMP1, implicating enhanced lysosomal function. No signs of retinal bleeding were observed after prolonged treatment with ticagrelor.ConclusionsOral treatment with ticagrelor protected photoreceptors in the ABCA4−/− mouse, which is consistent with enhanced lysosomal function. As mouse ticagrelor exposure levels were clinically relevant, the drug may be of benefit in preventing the loss of photoreceptors in Stargardt's disease and other neurodegenerations associated with lysosomal dysfunction.

YINGLONG: A Multicenter, Prospective, Non-Interventional Study Evaluating the Safety and Tolerability of Ticagrelor in Chinese Patients with Acute Coronary Syndrome.

IntroductionTicagrelor is an oral, reversible, direct-acting P2Y12 receptor inhibitor approved for the prevention of cardiovascular events in acute coronary syndrome (ACS). In China, drug intensive monitoring regulations for new drugs require additional safety data post-approval.MethodsYINGLONG, a single-arm, phase-IV, 1-year, non-interventional study, described the safety of ticagrelor 90 mg twice daily in Chinese patients (≥ 18 years) with ACS treated with ≥ 1 dose of ticagrelor. Primary outcomes were the incidence of adverse events (AEs), in particular, PLATelet inhibition and patient Outcomes (PLATO)-defined bleeding AEs, and other serious AEs during the 1-year follow-up. Key secondary outcomes were the incidence of major cardiovascular events.ResultsPatients (n = 1041, median age 61.0 years) had started ticagrelor and had post-dose data. Median duration of ticagrelor treatment was 357 days; 577 patients (55.4%) completed 1-year ticagrelor treatment; 973 patients (93.5%) completed 1-year follow-up. Overall, 38.7% of patients reported an AE during treatment. The most common AEs were dyspnea (n = 37, 3.6%), petechiae (n = 30, 2.9%), and chest discomfort (n = 28, 2.7%). Serious AEs, excluding bleeding, were reported in 9.8% of patients during treatment. Incidence of PLATO-defined major bleeding events was 1.1% (n = 11). Of the 21 deaths that occurred during the study (8 post-treatment), 1 was a fatal bleed. Major cardiovascular events were reported in 37 patients (3.6%).ConclusionsTicagrelor was well tolerated with a low rate of PLATO-defined major bleeding events in Chinese ACS patients. Safety results were consistent with the known ticagrelor profile.Trial RegistrationClinicalTrials.gov identifier, NCT02430493.FundingAstraZeneca Investment (China) Co., Ltd.Electronic supplementary materialThe online version of this article (10.1007/s12325-019-00972-z) contains supplementary material, which is available to authorized users.

Ticagrelor and cerebral hemorrhage: From a LC-MS/MS documented lethal intoxication to World Health Organization VigiBase® analysis

Ticagrelor is a direct and reversible competitive antagonist of the P2Y 12 receptor and inhibits platelet activation. From 2013 to 2016, 1027 ticagrelor-affiliated deaths were reported from 59 countries to the Food and Drug Administration and the trend is on the rise [1] . In order to highlight ticagrelor-related risk of hemorrhage, we report herein a documented lethal intoxication and a disproportionality analysis using World Heath Organization (WHO) VigiBase ® . A 47-year-old man died from a severe cerebral hemorrhage secondary to a fall and cranial trauma 4 days after an assumed massive ticagrelor intake. Iterative platelet transfusions did not improve his condition. Ticagrelor and its active metabolite AR-C124910XX plasma levels were determined by LC-MS/MS during patient hospitalization, using an Sciex API 3200 QTRAP mass spectrometer in negative electro-spray ionization mode [2] . Pharmacokinetics parameters were calculated using PK Solver ® 2.0. We performed a disproportionality analysis using VigiBase ® , the WHO pharmacovigilance database. Up to December 2018, more than 18 million Individual Case Safety Reports (ICSRs) have been collected from 131 countries. We extracted all the ICSRs with the MedDRA (version 21.1) preferred terms “cerebral hemorrhage” associated with antiplatelet agents, recorded from December 9, 1970 to December 16, 2018. LC-MS/MS toxicological analyses revealed high plasma concentrations of ticagrelor (3343 μg/L) and AR-C124910XX (656 μg/L) 10 h after the intake and remained quantifiable until patient death. Ticagrelor and AR-C124910XX elimination half-lives were 12.5 h and 32.8 h, respectively (normally 7.3 and 8.6 h). The ingested dose was therefore extrapolated to 1677 mg, which was a massive overdose (recommended dosage: 90 mg bid). In addition, the relationship between the use of ticagrelor and the occurrence of cerebral hemorrhage was assessed by calculating the reporting odds ratio (ROR) associated with its 95% confidence interval (CI) in a case-non-case model compared to other drugs. ROR value was significant (95% CI: lower boundary > 1 and ≥ 3 cases): ticagrelor ( n = 229, ROR = 8,01, 95% CI: 7,03–9,13), confirming that ticagrelor treatment is associated with intracerebral hemorrhage. Further studies are needed to better understand ticagrelor pharmacokinetics in cases of massive intoxication. These findings emphasized the need for a specific antidote to manage such complications resulting from ticagrelor overdose, but also the contribution of LC-MS/MS analysis to confirm a ticagrelor intoxication.

TREATMENT COMPLETION AND IMPLEMENTATION BY PATIENTS INITIATING TICAGRELOR.

In secondary prevention of adverse events and death following acute coronary syndrome, patients may benefit from adhering to a ticagrelor treatment. The authors assessed the proportion of new ticagrelor users who completed 12 months of treatment, explored the factors associated with treatment completion and, among the completers, evaluated the 12-month treatment implementation. A retrospective administrative health database inception cohort study was conducted in a population that included Quebec residents ≥18 years of age who initiated ticagrelor between January 1, 2012 and March 31, 2014. A patient still on ticagrelor at the end of the 12-month period after treatment initiation was considered to have completed the treatment. Factors associated with treatment completion were identified using log-binomial regression. Implementation was assessed using the proportion of days covered (PDC). Of the 3,600 patients, 2,235 (62.1%) completed 12 months of treatment. The patients who were more likely to complete their treatment included those who had visited a general practitioner, had a percutaneous coronary intervention, used a statin or fibrate, and those who used an antihypertensive drug during the year preceding the ticagrelor treatment initiation. Older patients, those with atrial fibrillation, those who had ≥ 6 physician visits and those who used an anticoagulant were less likely to complete the 12-month treatment. The median PDC was 96.2%. Treatment completion might be improved. Among patients who completed the treatment, implementation was high. The factors associated with completion could help to identify patients who might benefit from interventions that aim to optimize treatment completion.

Ticagrelor in patients with heart failure after acute coronary syndromes—Insights from the PLATelet inhibition and patient Outcomes (PLATO) trial

Heart failure (HF) following acute coronary syndromes (ACS) is associated with worse prognosis; however, the efficacy and safety of ticagrelor in patients with HF and if ticagrelor influences the risk of new-onset HF are unknown. We examined the efficacy and safety of ticagrelor compared to clopidogrel in patients with ACS in the randomized PLATelet inhibition and patient Outcomes (PLATO) trial subdivided by strata: (1) previous HF and/or clinical signs of HF on admission or (2) no HF on admission. The primary outcome was the combination of cardiovascular death, myocardial infarction, or stroke evaluated by multivariable Cox regression models. The safety outcome was major bleeding. New-onset HF was defined as an HF event after discharge in patients without previous HF. Data were available in 18,556 patients, whom 2,862 (15.4%) patients had HF, including 1,584 (8.5%) patients with previous HF. Patients randomized to ticagrelor had lower risk of the composite end point regardless of HF status: hazard ratio (HR) 0.87 (95% CI: 0.73-1.03) in patients with HF and HR 0.84 (95% CI: 0.75-0.93) in patients with no HF (P = .76). Corresponding HR for major bleeding were HR 1.08 (95% CI: 0.87-1.34) and HR 1.03 (95% CI: 0.94-1.14) (P = .71). There was no difference in new-onset HF at 12 months between patients randomized to ticagrelor (4.1%, n = 278) or clopidogrel (4.0%, n = 276). In patients with ACS, ticagrelor is more efficacious in protecting against new ischemic events and mortality than clopidogrel irrespective of the presence of HF. There is no difference between ticagrelor or clopidogrel treatment in new-onset HF post-ACS.

Effects of Ticagrelor versus Clopidogrel in Patients with Coronary Bifurcation Lesions Undergoing Percutaneous Coronary Intervention.

Background Percutaneous treatment of coronary bifurcation lesions can potentially lead to higher risk of ischemic events than the nonbifurcation ones, thus calling for further optimization of dual antiplatelet therapy (DAPT). This study aimed to compare the clinical outcomes from ticagrelor and clopidogrel in bifurcation lesions patients undergoing percutaneous coronary intervention (PCI). Methods We performed a retrospective cohort study in patients with coronary bifurcation lesions. A total of 553 patients discharged on ticagrelor or clopidogrel combined with aspirin were recruited for 1-year follow-up. The incidences of primary endpoint (major adverse cardiovascular event [MACE]: a composite of cardiac death, myocardial infarction [MI] or stroke), secondary endpoints (the individual component of the primary endpoint or definite/probable stent thrombosis), and major bleeding (Bleeding Academic Research Consortium [BARC]≥3 bleeding events) were evaluated. To minimize the selection bias, a propensity score-matched population analysis was also conducted. Results The risks of both primary endpoint (8.15% and 12.01% for the ticagrelor and clopidogrel groups, respectively; adjusted hazards ratio [HR]: 0.488, 95% confidence interval [CI]: 0.277-0.861, P=0.013) and MI (4.44% and 8.48% for the ticagrelor and clopidogrel groups, respectively; adjusted HR: 0.341, 95% CI: 0.162-0.719, P=0.005) were significantly reduced in the ticagrelor group as compared with those of the clopidogrel counterpart, whereas the risk of major bleeding was comparable (2.96% and 2.47% for the ticagrelor and clopidogrel groups, respectively; adjusted HR: 0.972, 95% CI: 0.321-2.941, P=0.960). Propensity score-matched analysis confirmed such findings. Conclusions For patients with bifurcation lesions after PCI, ticagrelor treatment shows lower MACE and MI rates than the clopidogrel one, along with comparable major bleeding.

Time to Loading Dose and Risk of Recurrent Events in the SOCRATES Trial.

Background and Purpose- Recurrent ischemia risk is high in the acute period after cerebral ischemic events. Effects of antiplatelet agents may vary by time to loading dose (TLD). We explored the risk of recurrent events and safety and efficacy of ticagrelor versus aspirin in relation to TLD. Methods- We randomized 13 199 patients with noncardioembolic, nonsevere ischemic stroke, or high-risk transient ischemic attack to 90-day ticagrelor or aspirin treatment within 24 hours of symptom onset. For this analysis, 13 126 patients were categorized by TLD as <12 hours or ≥12 hours from start of index event. The primary end point was the composite of stroke, myocardial infarction, or death within 90 days. Major bleeding was the primary safety end point. Results- TLD was <12 hours in 4403 (33.5%) and ≥12 hours in 8723 (66.5%). The Kaplan-Meier% for the primary end point for all patients with TLD<12 hours was 7.5% versus 6.9% in TLD≥12 hours. Among patients with TLD<12 hours, the primary end point occurred in 147/2196 (6.8%) randomized to ticagrelor and in 184/2207 (8.3%) randomized to aspirin (hazard ratio, 0.79; 95% CI, 0.64-0.98; P=0.036). Among patients with TLD≥12 hours, the primary end point occurred in 6.7% patients randomized to ticagrelor versus 7.0% to aspirin (hazard ratio, 0.95; 95% CI, 0.81-1.12; P=0.55). There was no significant treatment-by-TLD interaction. Major bleeding rates were comparable on ticagrelor and aspirin, regardless of TLD. Conclusions- The event rate for the primary end point was higher in patients treated early (<12 hours) versus later (≥12 hours). In this exploratory analysis, a larger numerical difference in the primary end point was observed among patients on ticagrelor than on aspirin when TLD was <12 hours compared with ≥12 hours, although the interaction terms for treatment-by-TLD were not significant. For major bleeding, no relation to TLD was observed. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01994720.

Dabigatran dual therapy with ticagrelor or clopidogrel after percutaneous coronary intervention in atrial fibrillation patients with or without acute coronary syndrome: a subgroup analysis from the RE-DUAL PCI trial.

AimsAfter percutaneous coronary intervention (PCI) in patients with atrial fibrillation, safety and efficacy with dabigatran dual therapy were evaluated in pre-specified subgroups of patients undergoing PCI due to acute coronary syndrome (ACS) or elective PCI, and those receiving ticagrelor or clopidogrel treatment.Methods and resultsIn the RE-DUAL PCI trial, 2725 patients were randomized to dabigatran 110 mg or 150 mg with P2Y12 inhibitor, or warfarin with P2Y12 inhibitor and aspirin. Mean follow-up was 14 months, 50.5% had ACS, and 12% received ticagrelor. The risk of the primary endpoint, major or clinically relevant non-major bleeding event, was reduced with both dabigatran dual therapies vs. warfarin triple therapy in patients with ACS [hazard ratio (95% confidence interval), 0.47 (0.35–0.63) for 110 mg and 0.67 (0.50–0.90) for 150 mg]; elective PCI [0.57 (0.43–0.76) for 110 mg and 0.76 (0.56–1.03) for 150 mg]; receiving ticagrelor [0.46 (0.28–0.76) for 110 mg and 0.59 (0.34–1.04) for 150 mg]; or clopidogrel [0.51 (0.41–0.64) for 110 mg and 0.73 (0.58–0.91) for 150 mg], all interaction P-values >0.10. Overall, dabigatran dual therapy was comparable to warfarin triple therapy for the composite endpoint of death, myocardial infarction, stroke, systemic embolism, or unplanned revascularization, with minor variations across the subgroups, all interaction P-values >0.10.ConclusionThe benefits of both dabigatran 110 mg and 150 mg dual therapy compared with warfarin triple therapy in reducing bleeding risks were consistent across subgroups of patients with or without ACS, and patients treated with ticagrelor or clopidogrel.

Optimising antiplatelet utilisation in the acute care setting: a novel threshold for medical intervention in suspected acute coronary syndromes

ObjectivesTo construct a model to optimise and personalise recommendations for antiplatelet prescription for patients with suspected acute coronary syndrome (ACS). Acknowledging that emergency physicians work with diagnostic uncertainty, we sought...

Temporal Variability of Platelet Reactivity in Patients Treated with Clopidogrel or Ticagrelor.

Background and ObjectivesThe degree of antiplatelet response to P2Y12 inhibitors has been associated with clinical outcomes. The aim of this study was to test the variability of platelet reactivity over time among patients treated with clopidogrel or ticagrelor.MethodsA single-center cohort of acute coronary syndrome patients that underwent percutaneous coronary intervention (PCI) was analyzed. Platelet reactivity was measured at baseline, 48 hours after PCI, 1 month, and 6 months after clopidogrel (n=79) or ticagrelor (n=93) treatment. High on-treatment platelet reactivity (HPR) was defined as ≥47 U, assessed by multiple electrode platelet aggregometry.ResultsPlatelet reactivity in the clopidogrel group increased over time, 38.2±21.7 U at 48 hours, 41.4±22.3 U at 1 month, and 44.7±25.5 U at 6 months (p=0.018, 48 hours to 6 months). However, platelet reactivity in the ticagrelor group was not significantly changed, 21.4±12.6 U at 48 hours, 20.0±12.2 U at 1 month, and 22.8±13.8 U at 6 months (p=0.392). A platelet reactivity change over time of more than 20U was found in 67.1% of the patients with clopidogrel group and 34.4% of ticagrelor group (p<0.001). Between 48 hours and 6 months, 43% of patients changed their responder status in the clopidogrel group, and 13% in the ticagrelor group (p<0.001).ConclusionsAlthough ticagrelor treatment resulted in less temporal variability of platelet reactivity than clopidogrel treatment in terms of HPR, platelet reactivity varied over time in a significant proportion of patients.

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