Ticagrelor overcomes high platelet reactivity in patients with acute myocardial infarction or coronary artery in-stent restenosis: a randomized controlled trial.
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ABSTRACT:
SUBMITTER: Li P
PROVIDER: S-EPMC4563354 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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Project description:AimsTo characterize ticagrelor exposure-response relationship for platelet inhibition in patients with stable coronary artery disease (CAD) and a history of myocardial infarction (MI), using nonlinear mixed effects modelling and simulation.MethodsPlatelet function data were integrated with plasma concentration data of ticagrelor and its active metabolite AR-C1249010XX in a population pharmacokinetic (PK) and pharmacodynamic (PD) model, based on two clinical studies. In the ONSET/OFFSET study, PK and platelet function were assessed in 123 CAD patients receiving placebo, ticagrelor (180 mg followed by 90 mg twice daily) or clopidogrel (600 mg followed by 75 mg once daily). In the PEGASUS-TIMI 54 platelet function substudy, PK and platelet function were assessed during maintenance dosing in 180 prior MI patients receiving placebo, ticagrelor 60 mg or ticagrelor 90 mg twice daily.ResultsPlatelet inhibition by ticagrelor was described by a sigmoidal Emax model. On average, half maximal inhibition was reached at ticagrelor concentrations of 116 (RSE: 5.3%) nmol l-1 . Simulations showed that near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At simulated lower doses, platelet inhibition is overall reduced, more variable between patients, and show greater peak-to-trough variability. Ticagrelor antiplatelet response was similar between the studied patient populations.ConclusionsIn patients with stable CAD or a history of MI, near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At modelled doses <60 mg, the response is reduced overall, more variable between patients, and patients will display greater peak-to-trough variability.
| S-EPMC6339964 | biostudies-literature
Project description:Transition from cangrelor to oral P2Y12 inhibitors after PCI carries the risk of platelet function recovery and acute stent thrombosis. Whether the recommended transition regimen is appropriate for hypothermic cardiac arrest survivors is unknown. We assessed the rate of high platelet reactivity (HPR) after transition from cangrelor to ticagrelor in hypothermic cardiac arrest survivors. Adult survivors of out-of-hospital cardiac arrest with ST-segment elevation myocardial infarction (STEMI), who were treated for hypothermia (33 °C ± 1) and received intravenous cangrelor during PCI and subsequent oral loading with 180mg ticagrelor were enrolled in this prospective observational cohort study. Platelet function was assessed using whole blood aggregometry. HPR was defined as AUC > 46U. The primary endpoint was the rate of HPR (%) at predefined time points during the first 24 h after cangrelor cessation. Poisson regression was used to estimate the relationship between the overlap time of cangrelor and ticagrelor co-administration and the number of subsequent HPR episodes, expressed as incidence rate ratio (IRR) with 95% confidence interval (95%CI). Between December 2017 and October 2019 16 patients (81% male, 58 years) were enrolled. On average, ticagrelor was administered 39 min (IQR 5-50) before the end of cangrelor infusion. The rate of HPR was highest 90 min after cangrelor cessation and was present in 44% (7/16) of patients. The number of HPR episodes increased significantly with decreasing overlap time of cangrelor and ticagrelor co-administration (IRR 1.03, 95%CI 1.01-1.05; p = 0.005). In this selected cohort of hypothermic cardiac arrest survivors who received cangrelor during PCI, ticagrelor loading within the recommended time frame before cangrelor cessation resulted in a substantial amount of patients with HPR.
| S-EPMC7073541 | biostudies-literature
Project description:High platelet reactivity (HPR) is a risk factor for stent thrombosis, a potentially lethal complication of percutaneous coronary intervention. HPR is also associated with increased risk of myocardial infarction and death in invasively-treated patients with acute coronary syndrome (ACS). HPR occurs even in ACS patients treated with ticagrelor, a state-of-the-art antiplatelet agent, especially during the first hours of treatment. Patient-level pharmacodynamic data obtained from 102 ACS subjects enrolled in two prospective, pharmacodynamic trials were analysed in order to identify clinical features related with increased odds of on-ticagrelor HPR during the first two hours after ticagrelor loading dose in ACS patients. Presence of ST-segment elevation myocardial infarction (versus non-ST-segment elevation ACS) and morphine co-administration were the strongest predictors of HPR at 1 and 2 hours after ticagrelor loading dose according to linear regression analyses, multiple backward stepwise logistic regression analyses and generalized estimating equation model. By pinpointing simple to recognize clinical features, the results of this study facilitate identification of ACS patients who have the highest odds of HPR during the initial phase of treatment with ticagrelor, and who could potentially benefit from alternative treatment strategies.
| S-EPMC6408477 | biostudies-literature
Project description:Atherosclerotic coronary artery disease (CAD) comprises a broad spectrum of clinical entities that include asymptomatic subclinical atherosclerosis and its clinical complications, such as angina pectoris, myocardial infarction (MI) and sudden cardiac death. CAD continues to be the leading cause of death in industrialized society. The long-recognized familial clustering of CAD suggests that genetics plays a central role in its development, with the heritability of CAD and MI estimated at approximately 50% to 60%. Understanding the genetic architecture of CAD and MI has proven to be difficult and costly due to the heterogeneity of clinical CAD and the underlying multi-decade complex pathophysiological processes that involve both genetic and environmental interactions. This review describes the clinical heterogeneity of CAD and MI to clarify the disease spectrum in genetic studies, provides a brief overview of the historical understanding and estimation of the heritability of CAD and MI, recounts major gene discoveries of potential causal mutations in familial CAD and MI, summarizes CAD and MI-associated genetic variants identified using candidate gene approaches and genome-wide association studies (GWAS), and summarizes the current status of the construction and validations of genetic risk scores for lifetime risk prediction and guidance for preventive strategies. Potential protective genetic factors against the development of CAD and MI are also discussed. Finally, GWAS have identified multiple genetic factors associated with an increased risk of in-stent restenosis following stent placement for obstructive CAD. This review will also address genetic factors associated with in-stent restenosis, which may ultimately guide clinical decision-making regarding revascularization strategies for patients with CAD and MI.
| S-EPMC4728103 | biostudies-literature
Project description:ObjectivesThe goal of this study was to determine whether ticagrelor reduces high-sensitivity troponin I concentrations in patients with established coronary artery disease and high-risk coronary plaque.BackgroundHigh-risk coronary atherosclerotic plaque is associated with higher plasma troponin concentrations suggesting ongoing myocardial injury that may be a target for dual antiplatelet therapy.MethodsIn a randomized, double-blind, placebo-controlled trial, patients with multivessel coronary artery disease underwent coronary 18F-fluoride positron emission tomography/coronary computed tomography scanning and measurement of high-sensitivity cardiac troponin I. Patients were randomized (1:1) to receive ticagrelor 90 mg twice daily or matched placebo. The primary endpoint was troponin I concentration at 30 days in patients with increased coronary 18F-fluoride uptake.ResultsIn total, 202 patients were randomized to treatment, and 191 met the pre-specified criteria for inclusion in the primary analysis. In patients with increased coronary 18F-fluoride uptake (120 of 191), there was no evidence that ticagrelor had an effect on plasma troponin concentrations at 30 days (ratio of geometric means for ticagrelor vs. placebo: 1.11; 95% confidence interval: 0.90 to 1.36; p = 0.32). Over 1 year, ticagrelor had no effect on troponin concentrations in patients with increased coronary 18F-fluoride uptake (ratio of geometric means: 0.86; 95% confidence interval: 0.63 to 1.17; p = 0.33).ConclusionsDual antiplatelet therapy with ticagrelor did not reduce plasma troponin concentrations in patients with high-risk coronary plaque, suggesting that subclinical plaque thrombosis does not contribute to ongoing myocardial injury in this setting. (Dual Antiplatelet Therapy to Reduce Myocardial Injury [DIAMOND]; NCT02110303).
| S-EPMC7342015 | biostudies-literature
Project description:ObjectiveRelationship between microalbuminuria and worse outcome of coronary artery disease patients is discussed, but its underlying pathophysiological mechanism remains unclear. We investigated the role of microalbuminuria to the function of endothelial progenitor cells (EPCs), that might affect to outcome of acute myocardial infarction (AMI) patients.MethodsForty-five AMI patients were divided into two groups according to their urinary albumin excretion: normal (n = 24) and microalbuminuria (>30 mg/day, n = 21). At day-2 and day-7 after AMI onset, circulating-EPCs (CD34+ Flk1+) were quantified by flow cytometry. The number of lectin-acLDL-positive cultured-EPCs immobilized on fibronectin was determined. To assess the cellular senescence of cultured-EPCs, the expression level of sirtuin-1 mRNA and the number of SA-?-gal positive cell were evaluated. Angiographic late in-stent loss after percutaneous coronary intervention (PCI) was evaluated at a six-month follow-up.ResultsNo significant differences in coronary risk and the extent of myocardial damage were observed between the two groups. Late in-stent loss at the six-month follow-up was significantly higher in the microalbuminuria group (normal:microalbuminuria = 0.76±0.34:1.18±0.57 mm, p=0.021). The number of circulating-EPCs was significantly increased in microalbuminuria group at day-7, however, improved adhesion of EPCs was observed in normal group but not in microalbuminuria group from baseline to day-7 (+3.1±8.3:-1.3±4.4%: p<0.05). On the other hand, in microalbuminuria group at day-7, the level of sirtuin-1 mRNA expression of cultured-EPCs was significantly decreased (7.1±8.9:2.5±3.7 fold, p<0.05), which was based on the negative correlation between the level of sirtuin-1 mRNA expression and the extent of microalbuminuria. The ratio of SA-?-gal-positive cells in microalbuminuria group was increased compared to that of normal group.ConclusionsMicroalbuminuria in AMI patients is closely associated with functional disorder of EPCs via cellular senescence, that predicts the aggravation of coronary remodeling after PCI.
| S-EPMC4395282 | biostudies-literature
Project description:Little is known about cardiac adverse events among patients with nonobstructive coronary artery disease (CAD).To compare myocardial infarction (MI) and mortality rates between patients with nonobstructive CAD, obstructive CAD, and no apparent CAD in a national cohort.Retrospective cohort study of all US veterans undergoing elective coronary angiography for CAD between October 2007 and September 2012 in the Veterans Affairs health care system. Patients with prior CAD events were excluded.Angiographic CAD extent, defined by degree (no apparent CAD: no stenosis >20%; nonobstructive CAD: ?1 stenosis ?20% but no stenosis ?70%; obstructive CAD: any stenosis ?70% or left main [LM] stenosis ?50%) and distribution (1, 2, or 3 vessel).The primary outcome was 1-year hospitalization for nonfatal MI after the index angiography. Secondary outcomes included 1-year all-cause mortality and combined 1-year MI and mortality.Among 37,674 patients, 8384 patients (22.3%) had nonobstructive CAD and 20,899 patients (55.4%) had obstructive CAD. Within 1 year, 845 patients died and 385 were rehospitalized for MI. Among patients with no apparent CAD, the 1-year MI rate was 0.11% (n?=?8, 95% CI, 0.10%-0.20%) and increased progressively by 1-vessel nonobstructive CAD, 0.24% (n?=?10, 95% CI, 0.10%-0.40%); 2-vessel nonobstructive CAD, 0.56% (n?=?13, 95% CI, 0.30%-1.00%); 3-vessel nonobstructive CAD, 0.59% (n?=?6, 95% CI, 0.30%-1.30%); 1-vessel obstructive CAD, 1.18% (n?=?101, 95% CI, 1.00%-1.40%); 2-vessel obstructive CAD, 2.18% (n?=?110, 95% CI, 1.80%-2.60%); and 3-vessel or LM obstructive CAD, 2.47% (n?=?137, 95% CI, 2.10%-2.90%). After adjustment, 1-year MI rates increased with increasing CAD extent. Relative to patients with no apparent CAD, patients with 1-vessel nonobstructive CAD had a hazard ratio (HR) for 1-year MI of 2.0 (95% CI, 0.8-5.1); 2-vessel nonobstructive HR, 4.6 (95% CI, 2.0-10.5); 3-vessel nonobstructive HR, 4.5 (95% CI, 1.6-12.5); 1-vessel obstructive HR, 9.0 (95% CI, 4.2-19.0); 2-vessel obstructive HR, 16.5 (95% CI, 8.1-33.7); and 3-vessel or LM obstructive HR, 19.5 (95% CI, 9.9-38.2). One-year mortality rates were associated with increasing CAD extent, ranging from 1.38% among patients without apparent CAD to 4.30% with 3-vessel or LM obstructive CAD. After risk adjustment, there was no significant association between 1- or 2-vessel nonobstructive CAD and mortality, but there were significant associations with mortality for 3-vessel nonobstructive CAD (HR, 1.6; 95% CI, 1.1-2.5), 1-vessel obstructive CAD (HR, 1.9; 95% CI, 1.4-2.6), 2-vessel obstructive CAD (HR, 2.8; 95% CI, 2.1-3.7), and 3-vessel or LM obstructive CAD (HR, 3.4; 95% CI, 2.6-4.4). Similar associations were noted with the combined outcome.In this cohort of patients undergoing elective coronary angiography, nonobstructive CAD, compared with no apparent CAD, was associated with a significantly greater 1-year risk of MI and all-cause mortality. These findings suggest clinical importance of nonobstructive CAD and warrant further investigation of interventions to improve outcomes among these patients.
| S-EPMC4893304 | biostudies-literature
Project description:Aims: In this pre-specified analysis of the "endothelium, stent and antiplatelet therapy" study, we investigate the impact of antiplatelet therapies on microvascular function in patients undergoing stenting for an acute coronary syndrome. Methods and Results: Fifty-six patients [age: 63(55-67) years, males, 10 diabetics, 27 non-ST-elevation myocardial infarction] were randomized to receive clopidogrel, ticagrelor or prasugrel in form of oral loading 2 h before stenting followed by oral therapy. Investigators were blinded to the allocation. Laser-Doppler microvascular function and ADP-induced platelet aggregation capacity were measured at baseline, 2 h after oral antiplatelet loading, and 1 day, 1 week and 1 month after stenting during chronic therapy with the same antiplatelet agent. Platelet aggregation decreased in all groups 2 h after oral loading, with a significantly larger effect in the prasugrel group (P = 0.009). Similarly, prasugrel and ticagrelor loading was followed by an increase in microvascular reactive hyperemia (P = 0.007 and P = 0.042 compared to clopidogrel). This effect disappeared one day after coronary intervention, with a significant decrease in the prasugrel group (P = 0.026). Similarly, analysis of microvascular conductance showed a larger increase in the prasugrel group 2 h after loading (P = 0.022 among groups), and a decrease in all groups after stenting. Conclusions: Oral loading with prasugrel (and less consistently ticagrelor) is associated with improved microvascular function and stronger platelet inhibition in acute coronary syndrome patients. The microvascular effect was however lost 1 day after stenting and during subsequent follow-up. Further studies are necessary to clarify the the long-term effects and potential benefits of P2Y12 inhibitors on microvascular damage. ClINICALTRIALS.gov N°: NCT01700322 EUDRACT-N°: 2011-005305-73.
| S-EPMC8710519 | biostudies-literature
Project description:In patients with acute coronary syndrome, high platelet reactivity (PR) is associated with an increased risk of secondary thrombotic events. However, in patients undergoing elective percutaneous coronary intervention (PCI), no association between high PR and outcome has been demonstrated. At present, the relation of PR and clinical symptoms is unknown. To examine the association of PR with clinical indication for diagnostic angiography (stable or unstable coronary artery disease [CAD]), taking into account the influence of P2Y12 inhibitors. A platelet function score (PFS) was determined in 195 patients by quantifying fibrinogen binding and P-selectin expression with flow cytometry. We evaluated the PFS with clinical presentation of stable or unstable CAD, angiographic severity of CAD, and the incidence of cardiovascular events during 2 years of follow-up. All data were analyzed stratified by P2Y12 inhibitor use (long-term and preprocedural versus none). Surprisingly, among non-P2Y12 inhibitor users, the PFS was lower in patients with unstable CAD compared with stable CAD (5.6?±?1.8 vs. 7.4?±?1.6; p?=?0.001). Angiographic CAD severity showed no relation with PFS. The SYNTAX score tended to be inversely related with PFS: low PFS, 13.2 (IQR, 11.9-19.1); median PFS, 10.0 (IQR, 5.0-14.0); and high PFS, 8.0 (IQR, 5.0-13.0), without significance (p?=?0.304). Patients with low PFSs required more re-PCIs than those with median and high PFSs (11.1 vs. 4.7 vs. 0.0%, p?=?0.004). This association was modified for patients using P2Y12 inhibitors. Among patients without P2Y12 inhibitors undergoing coronary angiography, presentation of unstable CAD is independently associated with lower PR.
| S-EPMC5114132 | biostudies-literature
Project description:Coronary artery disease (CAD) is the leading cause of mortality worldwide. We aimed to compare expression of miRNA in the affected artery of acute myocardial infarction (ST-elevation myocardial infarction) male patients versus healthy individuals (control). Blood samples were collected during coronary catheterization from proximal culprit coronary arteries aimed for the interventions or from a random artery in control samples. RNA isolated from serum was used for miRNA high throughput sequencing.
2023-04-23 | GSE230165 | GEO