Ticagrelor Treatment Research Articles

Ticagrelor vs. clopidogrel in ST elevation myocardial infarction patients with hemoglobin > 160

Abstract Background While some studies have provided therapeutic guidance for antiplatelet therapy in acute coronary syndrome (ACS) patients with anemia, research regarding ACS patients with elevated hemoglobin remains scarce. Purpose This study aims to evaluate the prognostic impact of different dual antiplatelet therapy (DAPT) regimens in ST-segment elevation infarction (STEMI) patients with hemoglobin > 160 g/L. Methods The data for this study were derived from the Health and Medical Big Data Superplatform, comprising a retrospective cohort of patients admitted to and discharged from 72 secondary and tertiary hospitals from 2010 to 2023. A total of 3372 patients were included in the study. Patients were divided into either the ticagrelor group or the clopidogrel group based on their priscribed antiplatelet regimens. The primary endpoint was defined as major adverse cardiovascular and cerebrovascular events (MACCE), comprising of cardiac death, myocardial infarction, and ischemic stroke within one month. Secondary endpoints included all-cause death at one-year, net adverse clinical events (NACE) defined as cardiac death, recurrent MI, Bleeding Academic Research Consortium (BARC) level 3 or greater, and revascularization, and cardiac death at one year. Propensity score matching (PSM) was utilized to balance clinical characteristics between the two groups. Multivariable Cox regression analysis was conducted post PSM to evaluate the impact of different antiplatelet regimens. Result The study population comprised 3372 patients, with 2200 receiving clopidogrel and 1172 with ticagrelor. The median age in the clopidogrel group was 54.83 years, while in the ticagrelor group, it was 53.61 years (P = 0.005). The clopidogrel group had a higher proportion of females compared to the ticagrelor group (3.9% vs. 2.0%, p=0.003). After PSM, 1086 well-matched pairs were identified. The ticagrelor group demonstrated a significantly lower rate of one-year all-cause mortality (1.38% VS 2.85%, LogRank p = 0.018), MACCE events (6.53% VS 9.48%, LogRank p = 0.015), and cardiac death (1.29% VS 2.76%, LogRank p = 0.015), compared to the clopidogrel group. However, there was no significant difference in the incidence of NACE events between the two groups (8.38% VS 7.76%, p = 0.300). Multivariate Cox regression analysis showed that ticagrelor treatment was associated with a reduced risk of all-cause mortality ( aHR 0.408, 95%CI: 0.214-0.775, p = 0.006), MACCE events (aHR 0.640, 95%CI: 0.473-0.869, p = 0.042), cardiac death (aHR 0.384, 95%CI: 0.198-0.743, p = 0.004). Conclusions Among STEMI patients with hemoglobin > 160 g/L, treatment with ticagrelor was associated with significantly lower rates of all-cause mortality, MACCE, and cardiac death compared to the treatment with clopidogrel.

Ticagrelor versus Clopidogrel in Patients with left main Coronary Artery Stenting.

The left main (LM) coronary artery disease poses high risks for its special anatomical characteristics. Optimal antiplatelet therapy is still controversial in this disease. We aimed to investigate the efficacy and safety of ticagrelor and clopidogrel in patients with stent implantation in the LM coronary artery. We analyzed 3221 patients with stent implantation in the LM coronary artery from January 2011 to June 2022. Patients were separated into two groups: the ticagrelor group (n = 1550) and the clopidogrel group (n = 1671). Baseline data were balanced by propensity score matching. The primary endpoint was all-cause mortality, and secondary endpoints included cardiovascular death, myocardial infarction, stroke, stent thrombosis, or target vessel revascularization. The primary safety endpoint was major bleeding, defined as BARC 3, 5 bleeding. After propensity score matching (n = 1228 in each group), ticagrelor was linked to a lower incidence of all-cause mortality compared with clopidogrel after a three-year follow-up (5.7% vs. 8.5%; HR:0.728; 95%CI:0.537-0.985, P = 0.040). Ticagrelor treatment reduced target lesion revascularization (3.3% vs. 6.4%; HR: 0.542; 95%CI: 0.371-0.791, P = 0.001) and stent thrombosis (1.6% vs. 3.7%; HR: 0.459; 95%CI: 0.271-0.776, P = 0.004). There was no significant difference in major bleeding between the two groups. Multivariate COX analysis suggested that age, heart rate, diabetes, prior myocardial infarction, hemoglobin, serum creatinine, ticagrelor, DAPT duration, LM true-bifurcation, LM stent diameters, and IVUS were independent predictive parameters of all-cause death. Ticagrelor was associated with lower all-cause mortality and no increased risk of major bleeding compared to clopidogrel in LM stenting patients. Thus, ticagrelor can be considered a viable substitute for clopidogrel in LM disease.

Subgroup effects of ticagrelor treatment strategies: credibility considerations in an individual patient data meta-analysis.

Subgroup effects of ticagrelor treatment strategies: credibility considerations in an individual patient data meta-analysis.

Editorial : "Clinical impact of dyspnea after ticagrelor treatment and the effect of switching to clopidogrel in patients with myocardial infarction".

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Comparison of Ticagrelor with Clopidogrel on Coronary Microvascular Dysfunction Following Acute Myocardial Infarction Using Angiography-Derived Index of Microcirculatory Resistance.

This research aimed to assess the impact of ticagrelor and clopidogrel on coronary microvascular dysfunction (CMD) and prognosis following acute myocardial infarction (AMI), using the angiography-derived index of microcirculatory resistance (angio-IMR) as a non-invasive assessment tool. In this retrospective study, angio-IMR was performed to evaluate CMD before and after dual antiplatelet therapy (DAPT) with either ticagrelor (90mg twice daily, n = 184) or clopidogrel (75mg once daily, n = 72). The primary endpoint is the improvement of CMD evaluated by angio-IMR (delta angio-IMR) following DAPT. Secondary endpoints included myocardial reinfarction and readmission for heart failure during 2-year follow-up. Compared with clopidogrel, ticagrelor exhibited a significantly higher delta angio-IMR [- 3.09 (5.14) versus - 1.99 (1.91), P = 0.008], indicating a superior improvement of CMD with ticagrelor treatment. Multivariate Cox regression indicated that ticagrelor treatment was related to a reduced risk of readmission for heart failure [8 (4.3) versus 9 (12.5), adjusted HR = 0.329; 95% CI = 0.116-0.934; P = 0.018] and myocardial reinfarction [7 (3.8) versus 8 (11.1), adjusted HR = 0.349; 95% CI = 0.125-0.975; P = 0.026]. Furthermore, ticagrelor treatment serves as an independent predictor of readmission for heart failure (HR = 0.322; 95% CI = 0.110-0.943; P = 0.039). The results of this study indicate a potential association between ticagrelor treatment and improved CMD, as well as a reduced risk of cardiovascular events, including myocardial reinfarction and readmission for heart failure in AMI patients. Further randomized controlled trials are necessary to confirm the potential benefits of ticagrelor on CMD and cardiovascular prognosis. This clinical trial was registered in www. gov (NCT05978726).

Outcomes of Ticagrelor Versus High-dose Clopidogrel in CYP2C19 Intermediate Metabolizer Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndromes.

Guidelines on antiplatelet recommendation for CYP2C19 intermediate metabolizer (IM) havenotcometoanagreement. This study aimed to evaluate the clinical benefit of ticagrelor when compared with high-dose clopidogrel in CYP2C19 IM after percutaneous coronary intervention for acute coronary syndromes. Patients were enrolled according to CYP2C19 genotype and individual antiplatelet therapy. Patient characteristics and clinical outcomes were collected through electronic medical record system. The primary outcome was major adverse cardiac and cerebrovascular event (MACCE), namely a composite of death from cardiovascular causes, myocardial infarction, stroke, and stent thrombosis within 12 months. The secondary outcome was Bleeding Academic Research Consortium scale bleeding events within 12 months. The Cox proportional hazards regression model was performed, with inverse probability treatment weighting (IPTW) adjusting for potential confounders. A total of 532 CYP2C19 IM were enrolled in this retrospective single-center study. No statistically significant difference in incidence rate of MACCE was found between patients receiving ticagrelor versus clopidogrel (7.01 vs. 9.52 per 100 patient-years; IPTW-adjusted hazard ratio 0.71; 95% confidence interval: 0.32-1.58; adjusted log-rank P = 0.396), but the incidence rate of Bleeding Academic Research Consortium type 2, 3, or 5 bleeding events was statistically higher in the loss of function-ticagrelor group than in the loss of function-clopidogrel group (13.53 vs. 6.16 per 100 patient-years; IPTW-adjusted hazard ratio: 2.29; 95% confidence interval: 1.10-4.78; adjusted log-rank P = 0.027). Ticagrelor treatment in CYP2C19 IM resulted in a statistically higher risk of bleeding compared with high-dose clopidogrel, whereas a clear association between treatments and MACCE warrants further investigations.

Population pharmacokinetic study and application of ticagrelor and AR-C124910XX after percutaneous coronary intervention in Chinese patients with acute coronary syndrome.

This study aimed to understand the pharmacokinetics of ticagrelor in Chinese patients with acute coronary syndrome (ACS), identify influencing factors, and inform ticagrelor treatment optimization. Data from 195 ACS patients, including 491 plasma ticagrelor concentration timepoints and clinical information, were analyzed using NONMEN for pharmacokinetic (PK) parameter factors. The model underwent internal validation with bootstrap methodology. The PK curve of ticagrelor was well delineated using a one disposition compartment model with first-order absorption rate constant, 0.67/h. When the direct bilirubin levels and white plasma cell counts increased, female patients showed decreased glomerular filtration rate, decreased ticagrelor clearance rate, and increased exposure. When the direct bilirubin levels increased and body weight and hemoglobin decreased, rs6787801 was GG compared with AA and GA, the ticagrelor metabolite clearance rate decreased and exposure increased. The study offers key insights into ticagrelor's dose-exposure relationship post-percutaneous coronary intervention in ACS patients, highlighting factors critical for personalized treatment strategies.

Ticagrelor potentiates cardioprotection by remote ischemic preconditioning: the ticagrelor in remote ischemic preconditioning (TRIP) randomized clinical trial

ObjectiveRemote ischemic preconditioning (RIPC) reduces periprocedural myocardial injury (PMI) after percutaneous coronary intervention (PCI) through various pathways, including an adenosine-triggered pathway. Ticagrelor inhibits adenosine uptake, thus may potentiate the effects of RIPC. This randomized trial tested the hypothesis that ticagrelor potentiates the effect of RIPC and reduces PMI, assessed by post-procedural troponin release. MethodsPatients undergoing PCI for non-ST elevation acute coronary syndromes were 1:1 randomized to ticagrelor (TG-Group) or clopidogrel (CL-Group). Within each treatment, patients were 1:1 randomized to a RIPC (RIPC-Group) or a control group (CTRL-Group). The primary endpoint was the difference between post- and pre-procedural troponin at 24 h following PCI, termed deltaTnI. ResultsDuring a 12-month period, 138 patients were included in the study (34 in the CL-CTRL group, 34 in the TG-CTRL group, 35 in the CL-RIPC group, and 35 in the TG-CTRL group). There was a significant difference in deltaTnI between the study groups [ TG-RIPC:0.04 (0–0.16), CL-CTRL:0.10 (0.03–0.43), CLRIPC:0.11 (0.03–0.89), and TG-CTRL:0.24 (0.06–0.47); p = 0.007]. Eight patients (22.9%) in the TG-RIPC group developed type 4a myocardial infarction (MI), compared to 14 (40%) in the CL-RIPC group, 13 (38.2%) in the CL-CTRL group, and 19 (55.9%) in the TG-CTRL group (p = 0.048). A significant interaction between antiplatelet group allocation and RIPC on deltaTnI was observed [F (1,134) = 7.509; p = 0.007]. In multivariate analysis, the interaction between RIPC and ticagrelor treatment was independently associated with a lower incidence of Type 4a MI. ConclusionOur results demonstrate an interaction between ticagrelor and RIPC, which may potentiate the cardioprotective effects of RIPC during PCI by reducing PMI.

Clinical Impact of Dyspnea after Ticagrelor Treatment and the Effect of Switching to Clopidogrel in Patients with Myocardial Infarction.

Dyspnea is frequent during ticagrelor-based dual antiplatelet therapy (DAPT) for acute myocardial infarction (AMI). However, its clinical characteristics or management strategy remains uncertain. The study assessed 2,617 AMI patients from the Ticagrelor versus Clopidogrel in Stabilized Patients with AMI (TALOS-AMI) trial. Dyspnea during 1-month ticagrelor-based DAPT and following DAPT strategies with continued ticagrelor or de-escalation to clopidogrel from 1 to 12 months were evaluated for drug adherence, subsequent dyspnea, major adverse cardiovascular events (MACE), and bleeding events. Dyspnea was reported by 538 patients (20.6%) during 1 month of ticagrelor-based DAPT. Adherence to allocated DAPT over the study period was lower in the continued ticagrelor arm than the de-escalation to clopidogrel, particularly among the dyspneic population (81.1% vs. 91.5%, p < 0.001). Among ticagrelor-treated patients with dyspnea, those switched to clopidogrel at 1 month had a lower frequency of dyspnea at 3 months (34.3% vs. 51.7%, p < 0.001) and 6 months (25.5% vs. 38.4%, p = 0.002) than those continued with ticagrelor. In patients with dyspnea in their 1-month ticagrelor-based DAPT, de-escalation was not associated with increased MACE (1.3% vs. 3.9%, hazard ratio [HR]: 0.31, 95% confidence interval [CI]: 0.08-1.11, p = 0.07) or clinically relevant bleeding (3.2% vs. 6.2%, HR: 0.51, 95% CI: 0.22-1.19, p = 0.12) at 1 year. Dyspnea is a common side effect among ticagrelor-based DAPTs in AMI patients. Switching from ticagrelor to clopidogrel after 1 month in AMI patients may provide a reasonable option to alleviate subsequent dyspnea in ticagrelor-relevant dyspneic patients, without increasing the risk of ischemic events (NCT02018055).

Novel cancer-fighting role of ticagrelor inhibits GTSE1-induced EMT by regulating PI3K/Akt/NF-κB signaling pathway in malignant glioma

BackgroundGlioma is the most common malignant brain tumor of the central nervous system. Despite of the improvement of therapeutic strategy, the prognosis of malignant glioma patients underwent by STUPP strategy is still unexpected. Previous studies have suggested that ticagrelor exerted chemotherapeutic effects by inhibition of epithelial-mesenchymal transition (EMT) in various diseases including tumors. However, whether ticagrelor can exhibit the antitumor efficiency in glioma by affecting the EMT process is still unclear. In this study, we investigated the cancer-fighting role of ticagrelor and demonstrated its chemotherapeutic mechanism in glioma. Materials and methodsThe MTT assay was performed to detect the cytotoxicity of ticagrelor in glioma cells. We evaluated the expression of Ki67 in glioma cells by immunofluorescence assay after ticagrelor treatment. We conducted wound healing assay and transwell assay to determine the effects of ticagrelor on the migration and invasion of glioma cells. RNA-seq analysis was conducted to examine potential target genes and alternative signaling pathways for ticagrelor treatment. The expression levels of key EMT -related proteins were examined by Western blot experiment. ResultsTicagrelor inhibited the proliferation, migration and invasion of glioma cells with a favorable toxicity profile in vitro. Ticagrelor downregulated the expression of GTSE1 in glioma cells. RNA-seq analysis explored that GTSE1 acted as the potential target gene for ticagrelor treatment. Upregulation of GTSE1 antagonized the inhibitory effect of ticagrelor on the invasion of glioma and EMT progression by regulation of PI3K/Akt/NF-κB signaling pathway. And ticagrelor also exhibited the similar chemotherapeutic effect of glioma in vivo. ConclusionsTicagrelor as a potential chemotherapeutic option induced the inhibition of the GTSE1-induced EMT progression by regulation of PI3K/AKT/NF-κB signaling pathway.

Abstract 2136: The Effects Of Dual Antiplatelet Therapy On Neutrophil Function

Introduction: Dual anti-platelet therapy (DAPT) is routinely administered to inhibit platelet aggregation in acute myocardial infarction (AMI) and, in doing so, reduces the risk of recurrent adverse cardiovascular events. Alongside platelets, neutrophils are also key mediators of inflammation during AMI, both secreting cytokines and chemokines and producing Neutrophil Extracellular Traps (NETs). While DAPT is known to mediate off-target anti-inflammatory effects, the extent to which DAPT affects neutrophil function is not well understood. Objective: To investigate the effects of DAPT on neutrophil-mediated inflammation. Methods: Neutrophils were isolated from whole blood of ten healthy subjects pre- and post-DAPT (ticagrelor and aspirin) treatment and NET formation in response to classical NET-inducing agonists (PMA and ionomycin) was measured by SYTOX Green fluorescence and MPO activity. Cytokine and chemokine production following stimulation with an activating agonist (FSL-1) was measured by cytometric bead array and reported as median fluorescence intensity (MFI). DAPT was effective in inhibiting platelet aggregation in response to AA and ADP. Results: NET formation in response to ionomycin, but not PMA, was greater in DAPT-treated neutrophils compared to treatment-naïve neutrophils (69.9 % ± 30.66 SEM). Levels of inflammatory mediators were also markedly different pre- and post- DAPT treatment. For example, MFI of IL-8 was decreased by 18% ± 9.97 SEM post-DAPT compared with pre-DAPT MFI, while MFI of IL-12p and IFN-α were significantly increased (32.54% ± 12.12 SEM, 58.68% ± 18.72 SEM respectively) compared to pre-DAPT. Conclusion: DAPT primes neutrophils for inducing some, but not all, NETotic pathways and releasing some, but not all, inflammatory mediators. This suggests that our primary strategy for inhibiting platelet aggregation in AMI does not provide broad off-target anti-inflammatory effects on neutrophils. In fact, DAPT may encourage a pro-inflammatory neutrophil phenotype.

Comparative Effectiveness and Safety of Ticagrelor and Clopidogrel in Patients With or Without Chronic Liver Disease: A Nationwide Cohort Study

BackgroundAlthough the effectiveness and safety of ticagrelor versus clopidogrel may differ in patients with chronic liver disease, there is a scarcity of evidence comparing ticagrelor and clopidogrel in patients with chronic liver disease. We aimed to evaluate the risk of major adverse cardiovascular events (MACE) and major bleeding associated with ticagrelor versus clopidogrel in patients undergoing percutaneous coronary intervention (PCI) due to acute coronary syndrome by chronic liver disease status. MethodsUsing the Korean healthcare claim database, we included adult patients who underwent PCI and initiated ticagrelor or clopidogrel treatment within 7 days of an acute coronary syndrome diagnosis. Patients were classified into 2 mutually exclusive groups: patients with chronic liver disease and patients without chronic liver disease. Within each group, the hazard ratios (HRs) with 95% confidence intervals (CIs) of MACE and major bleeding associated with ticagrelor versus clopidogrel were calculated using a Cox proportional hazards model within a 1:1 propensity score (PS) matched cohort. ResultsThe final cohort included 14,261 and 148,535 patients with and without chronic liver disease, respectively. After PS matching, the risk of MACE (with chronic liver disease, HR: 1.01, 95% CI: 0.91-1.13; without chronic liver disease, HR: 1.02, 95% CI: 0.98-1.05; P for homogeneity: 0.865) and major bleeding (with chronic liver disease, HR: 1.07, 95% CI: 0.71-1.61; without chronic liver disease, HR: 1.32, 95% CI: 1.15-1.53; P for homogeneity: 0.342) for ticagrelor versus clopidogrel do not vary with chronic liver disease status. ConclusionsAmong acute coronary syndrome patients undergoing PCI, the use of ticagrelor versus clopidogrel was associated with a similar risk of MACE and an increased risk of major bleeding, but these risks did not vary with chronic liver disease status.

Comparison of ticagrelor and clopidogrel in anemic patients with acute coronary syndrome: efficacy and safety outcomes over one year.

This retrospective study aimed to investigate the potential impact of ticagrelor and clopidogrel treatment on cardiovascular outcomes in patients with anemia and acute coronary syndrome (ACS) and to provide insights into the optimal therapeutic approach for this vulnerable patient population. A retrospective research design was employed, involving patients diagnosed with ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI) between 2014 and 2021. Inclusion criteria required a hemoglobin level below 12mg/dL and a minimum 12-month P2Y12 inhibitor treatment. Comprehensive clinical, biochemical, and echocardiographic data were collected from the hospital's electronic repository. The primary efficacy endpoint was major adverse cardiovascular events (MACE), encompassing total mortality, cardiovascular mortality, reinfarction, ischemic stroke, and hemorrhagic stroke. Major hemorrhage was the primary safety endpoint. Secondary outcomes included total mortality, cardiovascular mortality, reinfarction, ischemic stroke, and hemorrhagic stroke, individually. Patients treated with ticagrelor (n = 118) and clopidogrel (n = 538) were compared. No significant difference was observed in major adverse cardiovascular events (MACE) and major bleeding between ticagrelor and clopidogrel treatment groups (MACE: clopidogrel 10.0% vs. ticagrelor 11.0%, p = 0.75; major bleeding: clopidogrel 2.8%, ticagrelor 2.5%, p = 0.88). Patients with hemoglobin levels ≤ 8mg/dL demonstrated significantly higher MACE and major bleeding rates in the ticagrelor group (p = 0.008 and p = 0.002, respectively). Among patients aged ≥ 75 years, ticagrelor treatment was associated with a higher risk of major bleeding (p = 0.04). Ticagrelor and clopidogrel exhibited comparable efficacy and safety outcomes in anemic ACS patients over a one-year period. Although ticagrelor demonstrated superiority in reducing ischemic events, it is crucial to recognize the limitations of retrospective studies in informing clinical practice. This study offers valuable insights into tailoring antiplatelet therapy for anemic ACS patients and provides guidance for personalized treatment strategies, acknowledging the hypothesis-generating nature of retrospective analyses.

Risk of Bleeding and Ischemia in Elderly East Asian Patients with Diabetes Mellitus Treated with either Clopidogrel or Ticagrelor: From the Korean Acute Myocardial Infarction Registry-V.

Prescribing a P2Y12 inhibitor for patients with diabetes mellitus (DM) and acute myocardial infarction (AMI) who have undergone percutaneous coronary intervention (PCI) is challenging because of the risk of bleeding and ischemia. We compared the risk of ischemia and bleeding between clopidogrel and ticagrelor in elderly East Asian patients with diabetes using the Korea Acute Myocardial Infarction Registry (KAMIR)-V data. This study included 838 patients enrolled in the KAMIR-V who were >75 years, had DM, AMI, and had undergone PCI. The patients were divided into two groups based on the treatment drug. After propensity score matching, 466 patients (ticagrelor: clopidogrel= 233:233) were included in the Cox regression analyses to determine the risk of bleeding and ischemia. The baseline characteristics were not different. The type of antiplatelet therapy did not affect the incidence of Bleeding Academic Research Consortium type ≥2 bleeding. There was no significant difference between ticagrelor and clopidogrel treatment outcomes with respect to ischemia risk. This prospective study of a Korean patient cohort (elderly Korean patients with DM) showed no differences in bleeding and ischemia risks based on the use of either ticagrelor or clopidogrel. Large scale randomized controlled trials are warranted to determine the optimal antiplatelet agents for these patients.

Impact of kidney function, ticagrelor and genetic polymorphism on high platelet reactivity

Abstract Background High platelet reactivity (HPR) is associated with worse clinical outcomes. Patients with chronic kidney disease (CKD) respond poorly to clopidogrel. The purpose was to investigate what is major determinant on HPR in CKD patients. Methods A total of 219 (139 normal kidney function, 80 CKD) patients who were treated with clopidogrel or ticagrlor were assessed platelet reactivity and genetic polymorphisms. Platelet function was evaluated by the VerifyNowTM P2Y12 assay. Genes tested were ABCB1, PON1, cytochrome P450 (CYP) 2C19, CYP2C9 and P2Y12. HPR was defined as P2Y12 reaction units ≥ 230. Results Platelet reactivity were significantly higher in patients with CKD compared to normal kidney function (288 ± 96 vs 223 ± 69, p &amp;lt; 0.01). But, there were no significant differences of genetic distribution between 2 groups. In patients with CKD and normal kidney function, CYP2C19 carriers had greater platelet reactivity during clopidogrel therapy but there were no differences during ticagrelor treatment regardless of CYP2C19 status (Figure). In multivariate analysis, CKD [hazard ratio (HR): 4.67 (2.27 – 9.78), p &amp;lt; 0.01], CYP2C19 carriers [HR: 2.81 (1.36 – 5.82), p &amp;lt; 0.01] and ticagrelor treatment [HR: 0.29 (0.18 – 0.48), p &amp;lt; 0.01] were significantly correlated with HPR. Conclusion Ticagrelor treatment achieved greater platelet inhibition in patients with CKD whereas CKD and CYP2C19 genotype were significantly correlated with HPR.

TCT-11 Clinical Impact of Dyspnea After Ticagrelor Treatment and the Effect of Switching to Clopidogrel in Patients With Myocardial Infarction

TCT-11 Clinical Impact of Dyspnea After Ticagrelor Treatment and the Effect of Switching to Clopidogrel in Patients With Myocardial Infarction

Comparison of Ticagrelor Monotherapy and Ticagrelor plus Aspirin Among Patients with Acute Coronary Syndrome Combined with High-Risk of Gastrointestinal Bleeding after PCI: a Retrospective Cohort Study.

No studies to date have specifically examined the efficacy of P2Y12 inhibitor monotherapy in acute coronary syndrome (ACS) patients exhibiting a high risk of gastrointestinal (GI) bleeding following percutaneous coronary intervention (PCI). This was a retrospective cohort study of ACS exhibiting a high GI bleeding risk after PCI admitted to the Affiliated Hospital of Jiangnan University from August 2016-December 2019. Of the 308 enrolled patients, 269 were found eligible and were assigned to the ticagrelor monotherapy (TIC) arm (n=128) and to ticagrelor plus aspirin(TIC+ASP) arm (n=141) treatment for a 1-year period. The primary study outcome was a composite endpoint including bleeding academic research consortium (BARC) type 2, 3, or 5 bleeding and adverse cardiac or cerebrovascular events. 8 (6.3%) in the TIC group and 14 (9.9%) in the combination treatment group reached the primary ischemic endpoint within 1 year with no significant difference between these groups. BARC type 2/3/5 bleeding events affected significantly more patients in the combination group relative to the TIC group (38[27.0%] vs 11[8.6%], P <0.001). As the follow-up interval was prolonged, the cumulative BARC type 2/3/5 bleeding incidence in the TIC group remained significantly below that in the combination treatment group (P<0.05). These results indicate that TIC is associated with a lower risk of clinically relevant bleeding events among ACS with a high risk of GI bleeding after PCI relative to combination TIC+ASP treatment, while ischemic outcomes in these two groups were similar.

Ticagrelor Treatment is Associated With Increased Coronary Flow Reserve in Survivors of Myocardial Infarction.

The pleiotropic action of ticagrelor, with effects in addition to platelet inhibition, has been shown to improve endothelial function in patients with coronary artery disease. These positive effects are possibly adenosine mediated. This study investigated the association of ticagrelor therapy and coronary artery flow reserve in survivors of myocardial infarction (MI). This was an exploratory, cross-sectional, open substudy of PROFLOW. High-risk individuals with a history of MI were identified. Coronary flow reserve (CFR) was measured non-invasively in the left anterior descending artery using transthoracic Doppler echocardiography. Coronary flow velocity was measured at rest and at maximal flow after induction of hyperaemia by intravenous infusion of adenosine at 140 μg/kg/min. Patients receiving ticagrelor (n=75) were compared with those not receiving ticagrelor (n=506), using simple and multiple linear regression models. Most patients in both groups were treated with aspirin (97% in the ticagrelor and 94% in the non-ticagrelor group). Adjustment for traditional risk factors was conducted. The mean age at study inclusion was 68.5±6.8 years, and most patients were male (81.8%). The simple linear regression analysis showed ticagrelor treatment to be significantly associated with increased CFR: ticagrelor 2.95±0.76 (mean±SD), non-ticagrelor 2.70±0.77, (coefficient 0.25; 95% CI 0.063-0.438; p=0.009). This association was significant in two of the three multiple linear regression models with increasing numbers of variables: Model 1 (0.28; 0.06-0.50; p=0.014), Model 2 (0.26; 0.03-0.48; p=0.025), and borderline significant in Model 3 (0.21; -0.01 to 0.43; p=0.058). Ticagrelor treatment was associated with increased CFR in this high-risk population. Increased CFR may be a clinically important therapeutic effect of ticagrelor in addition to platelet inhibition.

Abstract 140: A Common, Racially Diverse Protease Activated Receptor 4 Functional Variant Impacts Ischemic Stroke Outcomes: Evidence For A Pharmacogenetic Effect

Black individuals have a higher incidence of ischemic stroke (IS) than White individuals. The platelet receptor PAR4 harbors a functional dimorphism: rs773902 A/G (encoding Thr120/Ala120, respectively), and the A allele is associated with greater ex vivo platelet aggregation. The A allele frequency is 0.6 in Black individuals and 0.2 in White subjects. However, it is unknown whether the A allele contributes to racial differences in IS. In a prospective cohort, the REGARDS study, a Black subject-only analysis of 487 IS cases and 7,133 controls was performed, examining if the A allele was a risk for incident IS and worse IS outcome. We used Cox proportional hazards models to calculate hazard ratios (HR) with 95% confidence intervals (CI) of incident IS for the rs773902 A allele. Models were adjusted for age, sex, the first 5 genetic principal components, smoking, hypertension and diabetes. To directly test the effect of this PAR4 variant on IS, we generated the first humanized PAR4 (hPAR4) mouse strains expressing either hPAR4 Thr120 or hPAR4 Ala120. In REGARDS, the A allele was a risk factor for incident IS (HR 1.24; CI 1.04-1.53, p=0.046) and worse IS outcome (HR 2.04; CI 1.10-3.79, p=0.025). In a murine stroke model, hPAR4 Thr120 mice had worse stroke outcomes compared to hPAR4 Ala120 mice (60% increase, p=0.001). This phenotype was mediated, in part, by enhanced platelet activation (p=0.002), platelet-neutrophil interactions (p=0.014), and neutrophil extracellular traps (p=0.001). Direct inhibition of PAR4 with BMS-986120 was equally effective in improving stroke outcomes in hPAR4 Ala120 and Thr120 mice. In contrast, ticagrelor treatment improved stroke outcomes in hPAR4 Ala120 mice (50% decrease, p=0.007), but was ineffective in hPAR4 Thr120 mice, even when combined with aspirin. Importantly, blocking platelet-neutrophil interactions downstream of PAR4 with a murine analog of the FDA-approved P-selectin inhibitor crizanlizumab improved stroke outcomes in hPAR4 Thr120 mice (55% decrease, p=0.004). These results support a causal role for PAR4 Thr120 in IS that may explain part of the racial disparity in stroke. Our findings further suggest that different anti-platelet therapies may be needed for patients expressing PAR4 Thr120.

Effect of Savirin or Ticagrelor Treatment on the Expression of Commonly Used Reference Genes in Staphylococcus aureus

Reference genes are frequently used for the normalization of quantitative reverse transcriptase PCR (qRTPCR) data in gene expression studies. Staphylococcus aureus is one of the most common causes of biofilm-related infections. Savirin and ticagrelor show in vitro as well as in vivo antibiofilm activity against S. aureus. The main aim of this study was to identify the most stably expressed reference genes to study the effect of these molecules on genes in a strong biofilm producing S. aureus isolate isolated from biofilm-related infection. Quantitative real-time PCR was performed by using relative quantification method. Four different algorithms, delta Ct, normfinder, bestkeeper, and genorm, followed by a comprehensive analysis was used to identify the most stable reference genes from a list of sixteen different candidate reference genes. All four algorithms reported different results, with some comparable findings among some methods. In the comprehensive analysis of the results of all the algorithms used, the most stable reference genes found were spa, rpoD, and pyk for savirin treatment experiment and gapdH, gyrA, and gmk for ticagrelor treatment experiment. The optimal number of reference genes required was two for both the experimental conditions. Despite having some drawbacks, each algorithm can reliably determine an appropriate reference gene independently. However, based on consensus ranking and the required optimal number of reference genes reported, spa and rpoD were the most appropriate reference genes for savirin treatment experiment, and gapdH and gyrA were most appropriate for ticagrelor treatment experiment. This study provides baseline data on reference genes to study the effect of savirin or ticagrelor treatment on the expression of potential reference genes in S. aureus. We recommend prior re-validation of reference genes on a case-by-case basis before they can be used.