thienopyridine and Acute-Coronary-Syndrome

To investigate the effect of pretreatment with P2Y12 receptor inhibitors compared with no pretreatment on efficacy and safety of treatment of non-ST elevation acute coronary syndrome (ACS).. Two reviewers independently searched Medline, Embase, Cochrane Controlled Trials, and BioMed Central databases for randomized placebo controlled trials and observational studies from August 2001 to March 2014.. Studies must have reported both all-cause mortality (primary efficacy endpoint) and major bleeding (safety endpoint) outcomes.. Data on sample size, characteristics, drug dose and delay of administration, and outcomes were independently extracted and analyzed.. A random-effect model was applied. The analysis was performed (i) in all patients independently of the management strategy and (ii) only in patients undergoing percutaneous coronary intervention.. Of the 393 titles identified, seven (four randomized controlled trials, one observational analysis from a randomized controlled trial, and three observational studies) met the inclusion criteria. No study was identified for ticagrelor or cangrelor, and analyses were thus limited to thienopyridines. A total of 32,383 non-ST elevation ACS patients were included, 18,711 coming from randomized controlled trials. Of these, 55% underwent percutaneous coronary intervention (PCI). Pretreatment was not associated with a significant lower risk of mortality in all patients (odds ratio 0.90 (95% confidence interval 0.75 to 1.07), P=0.24), in particular when considering only the randomized controlled trials (odds ratio 0.90 (0.71 to 1.14), P=0.39). Similar results were observed in the cohort of patients undergoing PCI. A significant 30-45% excess of major bleeding was consistently observed in all patients (odds ratio 1.32 (1.16 to 1.49), P<0.0001) and in those undergoing PCI, as well as in the subset analyses of randomized controlled trials of these two cohorts of patients. There was a reduction in major adverse cardiovascular events in the analysis of all patients (odds ratio 0.84 (0.72 to 0.98), P=0.02), driven by the old clopidogrel studies (CURE and CREDO), but the difference was not significant for the cohort of patients undergoing PCI. Stent thrombosis, stroke, and urgent revascularization did not differ between groups (pretreatment v no pretreatment). The results were consistent for both thienopyridines and confirmed in sensitivity analyses.. Analysis was not performed on individual patient's data.. In patients presenting with non-ST elevation ACS, pretreatment with thienopyridines is associated with no significant reduction of mortality but with a significant excess of major bleeding no matter the strategy adopted, invasive or not. Our results do not support a strategy of routine pretreatment in patients with non-ST elevation ACS.

Topics: Acute Coronary Syndrome; Combined Modality Therapy; Drug Administration Schedule; Humans; Models, Statistical; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Pyridines; Treatment Outcome

Antithrombotics are one of the most commonly prescribed classes of medication around the world. The thienopyridines are an integral part of antithrombotic therapy and are prescribed for various indications including acute coronary syndrome, peripheral vascular disease and cerebrovascular disease. These drugs have distinct metabolic pathways, which lead to the formation of active metabolites that produce both observed clinical differences as well as pharmacokinetic and pharmacodynamic differences in response.. The authors describe the pharmacokinetic and pharmacodynamic behavior of three of the currently available thienopyridines, namely ticlopidine, clopidogrel and prasugrel. The authors also describe and discuss the drug interaction and pharmacogenomic factors which may impact safety and drug efficacy.. P2Y(12)-ADP receptor antagonism has proven to be effective at preventing thrombosis. Differences in the activation of these drugs, cytochrome metabolism, concomitant drug use and pharmacogenomics have an impact on thienopyridine use. Clopidogrel remains the thienopyridine drug with the most approved indications for use. Prasugrel has proven to be efficacious but is associated with a higher bleeding risk in comparison to clopidogrel and therefore has to be used in appropriate clinical indications.

Topics: Acute Coronary Syndrome; Aryl Hydrocarbon Hydroxylases; Clopidogrel; Cytochrome P-450 CYP2C19; Drug Interactions; Fibrinolytic Agents; Hemorrhage; Humans; Inactivation, Metabolic; Pharmacogenetics; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Pyridines; Thiophenes; Ticlopidine

Early studies of glycoprotein IIb/IIIa inhibitors (GPIs) demonstrated benefit during percutaneous coronary intervention for acute coronary syndromes (ACS). Since their introduction, the magnitude of benefit of GPIs has become unclear.. We hypothesized that adding a GPI to unfractionated heparin in ACS patients treated with stents and thienopyridines is beneficial.. We searched the MEDLINE, Cochrane, and clinicaltrials.gov databases for randomized clinical trials that studied the use of GPIs during ACS. We required that patients be randomly assigned to unfractionated heparin plus a GPI versus unfractionated heparin plus placebo (or control). Additional inclusion criteria included the use of coronary stents and periprocedural thienopyridines. Outcomes were assessed at 30 days. Random effects DerSimonian-Laird summary risk ratios (RR) and 95% confidence intervals (CIs) were constructed.. Sixteen studies with 7611 patients were included. Myocardial infarction was 3.1% with GPI versus 4.4% with control (RR = 0.74; 95% CI, 0.59-0.94, P = 0.014); revascularization, 1.7% versus 2.7% (RR = 0.64; 95% CI, 0.46-0.89, P = 0.008); major bleeding, 2.5% versus 2.1% (RR = 1.21; 95% CI, 0.89-1.63, P = 0.22); minor bleeding, 5.5% versus 4.1% (RR = 1.37; 95% CI, 1.06-1.78, P = 0.016); and mortality, 2.2% versus 2.9% (RR = 0.79; 95% CI, 0.59-1.06, P = 0.12), respectively.. Among ACS patients treated with stents and thienopyridines, GPIs were associated with reduced myocardial infarction and revascularization. Minor, but not major bleeding was increased with GPIs. Mortality was similar between the groups. © 2011 Wiley Periodicals, Inc. Supporting information may be found in the online version of this article This work was supported by an unrestricted grant from the Florida Heart Research Institute, which had no role in the study design, data collection, analysis, or interpretation, manuscript writing, or decision to proceed with publication. Anthony A Bavry has received research support from Novartis Pharmaceuticals and serves as a contractor for American College of Cardiology Cardiosource. The other authors have no funding, financial relationships, or conflicts of interest to disclose.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Anticoagulants; Drug Therapy, Combination; Hemorrhage; Heparin; Humans; Mortality; Myocardial Infarction; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyridines; Randomized Controlled Trials as Topic; Stents

Adenosine diphosphate (ADP)-induced platelet activation plays a pivotal role in the thrombocyte aggregation and pathogenesis of ischemic heart disease. The long-term benefit of dual anti-platelet therapy with ADP-receptor antagonists, such as clopidogrel, in combination with aspirin is well established for patients following coronary stent implantation. This review discusses latest developments in the field of ADP-receptor antagonists.

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Aspirin; Clopidogrel; Combined Modality Therapy; Humans; Myocardial Ischemia; Platelet Aggregation Inhibitors; Pyridines; Receptors, Purinergic P2; Stents; Ticlopidine

Ticlopidine, clopidogrel, and prasugrel are thienopyridine prodrugs that inhibit adenosine-5'-diphosphate (ADP)-mediated platelet aggregation in vivo. These compounds are converted to thiol-containing active metabolites through a corresponding thiolactone. The 3 compounds differ in their metabolic pathways to their active metabolites in humans. Whereas ticlopidine and clopidogrel are metabolized to their thiolactones in the liver by cytochromes P450, prasugrel proceeds to its thiolactone following hydrolysis by carboxylesterase 2 during absorption, and a portion of prasugrel's active metabolite is also formed by intestinal CYP3A. Both ticlopidine and clopidogrel are subject to major competing metabolic pathways to inactive metabolites. Thus, varying efficiencies in the formation of active metabolites affect observed effects on the onset of action and extent of inhibition of platelet aggregation (IPA). Knowledge of the CYP-dependent formation of ticlopidine and clopidogrel thiolactones helps explain some of the observed drug-drug interactions with these molecules and, more important, the role of CYP2C19 genetic polymorphism on the pharmacokinetics of and pharmacodynamic response to clopidogrel. The lack of drug interaction potential and the absence of CYP2C19 genetic effect result in a predictable response to thienopyridine antiplatelet therapy with prasugrel. Current literature shows that greater ADP-mediated IPA is associated with significantly better clinical outcomes for patients with acute coronary syndrome.

Topics: Acute Coronary Syndrome; Aryl Hydrocarbon Hydroxylases; Blood Platelets; Clopidogrel; Cytochrome P-450 CYP2C19; Drug Interactions; Humans; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Polymorphism, Genetic; Prasugrel Hydrochloride; Pyridines; Thiophenes; Ticlopidine

Inhibition of platelet aggregation (IPA) has been a drug development target in acute coronary syndrome (ACS) for almost 2 decades. The relationship between IPA and cardiovascular (CV) events has not been quantified. Cardiovascular (non fatal myocardial infarction, death) and major bleeding events were extracted from phase 2 or 3 randomized, double-blind trials that evaluated oral and intravenous glycoprotein 2b/3a (GP2b/3a) antagonists and thienopyridines. IPA was extracted from different sources that studied a similar regimen in a similar population. Events were correlated to IPA using a linear relative-risk mixed-effects model. Covariates included type of drug, mean age, gender percentage, and ADP. Clinical trial simulations were conducted to evaluate the relationship between IPA and the likelihood of observing a CV event in a 6-month end point trial. Data from 81918 subjects in 20 studies were extracted from the literature. To achieve a 20% relative reduction in CV events would require a further 77% (56%-100%) absolute increase in IPA for IV GP2b/3a antagonists or a further 27%(20%-41%) absolute increase for thienopyridines. CV risk reduction was less in studies with older subjects and greater in studies with greater percentages of male subjects. Assuming a 3% major bleeding rate in the control group, these drugs had a 1% increase in absolute risk as absolute platelet inhibition increases by 60% (range, 40%-80%). This relationship in intrinsic bleeding may be different in different population subtypes. Assuming a 12% event rate, a 6-month active-controlled thienopyridine trial with 3000 subjects could detect a relationship between CV events and IPA with 80% likelihood. Target IPA increases in ACS are an absolute increase of 80% for IV GP2b/3a antagonists and 30% for thienopyridines. Quantitative models using literature data on IPA and CV events can be used to select dose regimens in early stages of drug development.

Topics: Acute Coronary Syndrome; Age Factors; Biomarkers; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Hemorrhage; Humans; Models, Biological; Myocardial Infarction; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyridines; Randomized Controlled Trials as Topic; Risk Assessment; Sex Factors

Acute coronary syndrome (ACS) is associated with a persistent prothrombotic state, placing patients at high risk of subsequent ischemic events. Guidelines recommend the use of dual antiplatelet therapy with aspirin + a thienopyridine (clopidogrel) for at least a year after ACS in most patients, except those who undergo coronary artery bypass grafting. Clinical studies demonstrate that this strategy significantly reduces the risk of ischemic events at the expense of a small increase in the risk of bleeding. Physicians must balance the risk of bleeding against the benefit of ischemia prevention, bearing in mind that ischemic events are generally more common than major bleeding and often associated with more catastrophic consequences or ongoing morbidity. The relationship between bleeding and mortality is complicated by the fact that many risk factors for bleeding are also those for mortality and that bleeding may lead to discontinuation of antiplatelet therapy, thereby increasing the risk for an ischemic event. Data suggest that physicians tend to overestimate the risk of bleeding and underestimate the risk of ischemia. Careful patient selection and thorough patient education are the keys to managing antiplatelet therapy after ACS, especially as newer more potent antiplatelet agents, such as prasugrel, become available.

Topics: Acute Coronary Syndrome; Aspirin; Clinical Trials as Topic; Clopidogrel; Coronary Artery Bypass; Hemorrhage; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Risk Factors; Thiophenes; Thrombosis; Ticlopidine

In a series of articles the authors consider clinical pharmacology and experience of clinical application of blockers of platelet P2Y12 receptors, most well known representatives of which ticlopidine and clopidogrel according to chemical structure belong to thienopyridine derivatives. In the fifth communication we consider data of two randomized studies in which efficacy and safety of clopidogrel in combination with acetylsalicylic acid (ASA) has been assessed in comparison with ASA in stable patients with atherothrombotic cardiovascular disease. It has been shown in both studies that in stable patients with atherothrombotic cardiovascular disease long-term therapy with combination of clopidogrel and ASA was no more effective than monotherapy with ASA or clopidogrel but was associated with high risk of hemorrhagic complications. Thus contrary to acute coronary syndromes and percutaneous interventions with stenting combinations of clopidogrel and ASA is not indicated to patients with stable course cardiovascular diseases.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Arteriosclerosis; Aspirin; Cardiovascular Diseases; Clopidogrel; Coronary Circulation; Death, Sudden, Cardiac; Drug Therapy, Combination; Fibrinolytic Agents; Hemorrhage; Humans; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Risk Factors; Sex Factors; Streptokinase; Stroke; Thrombosis; Ticlopidine; Time Factors

Dual antiplatelet therapy with a thienopyridine in combination with aspirin for 1 to 6 months after stenting has been recommended by the manufacturers to reduce ischemic cardiovascular events and thrombosis after coronary stenting, whereas the current leading guidelines recommend dual antiplatelet therapy for 12 months following percutaneous coronary intervention in all patients not at high risk of bleeding. Despite the established benefits of dual antiplatelet therapy in acute coronary syndrome (ACS) patients, there are concerns regarding the risk of major bleeding. The risks, benefits, and complexity identified in these interventional trials are communicated in this article to enable well-informed therapeutic decisions. Thienopyridine nonresponsiveness and variability of response are emerging as significant concerns in ACS patients that may lead to poor long-term cardiovascular outcomes. Current research on thienopyridine responsiveness and evidence-based mechanisms for overcoming thienopyridine nonresponsiveness are discussed. In addition, adherence to dual antiplatelet therapy is critical but difficult to achieve, and a considerable proportion of patients (1 of 7) discontinue therapy before 30 days of drug-eluting stent implantation. It has been established that premature discontinuation of thienopyridine therapy is associated with a marked increase in the risk of stent thrombosis (and consequently myocardial infarction and/or death) and is the leading independent predictor of stent thrombosis in multivariate analyses. The factors related to premature cessation of thienopyridine therapy are listed with recommendations for minimizing the complications arising as a result of premature discontinuation.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Aspirin; Fibrinolytic Agents; Humans; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Pyridines; Stents; Time Factors

This article reviews the currently available antiplatelet therapies and emerging investigational drugs in the treatment of acutecoronary syndrome (ACS), and considerations for primary and secondary prevention in the long-term management of ACS patients undergoing percutaneous coronary intervention (PCI).. Primary studies and reviews in the peer-reviewed, English-language literature were identified through searches of MEDLINE (1966-2008) using the terms 'acute coronary syndrome', 'antiplatelet', 'aspirin', 'long-term management', 'P2Y(12) receptor', and 'thienopyridine'. Additional references were obtained by searching the reference lists of the identified articles. Articles were included if they were recently published and pertinent, patient-focused, and authors were recognized as leaders in the field. Current review is limited by literature search on single database.. Platelets play a major role in atherogenesis and the formation of thrombi, the main events in the pathogenesis of ACS. Although aspirin is an effective antiplatelet agent, efficacy and safety data from a number of randomized clinical trials on atherothrombotic disease support the use of dual antiplatelet therapies such as aspirin and thienopyridines over single antiplatelet therapy for ACS and up to 1 year following ACS. Antiplatelet agents reduce, but do not eliminate, ischemic events after ACS due, in part, to variable individual response (or resistance) in antiplatelet agents, non-compliance, progression of atherosclerosis, modest inhibition of platelet aggregation (IPA) levels and other factors. Several antiplatelet agents, including novel P2Y(12)-receptor antagonists and thrombin-receptor antagonists, are currently under investigation for ACS and primary and secondary prevention in the long-term management of patients undergoing PCI.. Current antiplatelet therapies have clinical benefits such as reducing immediate and long-term cardiovascular risk, but substantial residual risk remains indicating a need for new therapeutic agents. Additional large randomized trials are necessary to determine the most appropriate treatment regimens for ACS patients.

Topics: Acute Coronary Syndrome; Algorithms; Clinical Trials as Topic; Guidelines as Topic; Humans; Long-Term Care; Models, Biological; Platelet Aggregation Inhibitors; Pyridines

Oral antiplatelet therapy has been very effective in reducing vascular events. Currently available oral antiplatelet agents are aspirin and the thienopyridine P2Y(12)-receptor antagonists. These agents are used frequently in combination among patients with coronary artery disease, and also following percutaneous coronary intervention to reduce major adverse cardiovascular events. Emergence of resistance to either aspirin or clopidogrel, or both the agents, is a major concern as antiplatelet resistance is likely to increase thrombotic events, thus resulting in a worse clinical outcome. Development of new agents has therefore become imperative. Prasugrel is the newest thienopyridine with the most robust clinical data, and appears to be superior to clopidogrel, the most extensively used agent besides aspirin in contemporary cardiovascular practice. Possible advantages of prasugrel over clopidogrel are its faster onset of action, reduced inter-patient variability, and more potent and persistent platelet inhibition. This article summarizes the available clinical data on prasugrel in the treatment of coronary artery disease.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Aspirin; Clopidogrel; Drug Resistance; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Thiophenes; Ticlopidine

Since the development and market entry of clopidogrel, a platelet ADP blocker, physicians have had few new antiplatelet options available to them for the treatment of acute and chronic coronary disease, specifically in the setting of acute coronary syndromes, percutaneous coronary intervention, and chronic stent management. Over the years, limitations of current antiplatelet regimens have emerged, establishing a need for novel antiplatelet drugs. This article discusses potential new targets for platelet inhibition and reviews innovative antiplatelet therapies under investigation.. There are five main categories of antiplatelet therapies currently undergoing clinical study, consisting of the thienopyridines (P2Y12 receptor antagonists), cyclopentyltriazolopyrimidines (P2Y12 receptor antagonists), anti-von Willebrand factor aptamers, thrombin receptor (protease-activated receptor-1) antagonists, and thromboxane receptor antagonists. Early studies of these agents are discussed.. Each of these new antiplatelet therapies has a unique profile that is aimed at improving clinical response with hopes of incremental efficacy and decreased complications, specifically bleeding.

Topics: Acute Coronary Syndrome; Aspirin; Clopidogrel; Humans; Myocardial Infarction; Platelet Aggregation Inhibitors; Pyridines; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Receptors, Thrombin; Ticlopidine; von Willebrand Factor

Currently, clopidogrel is recommended for treatment of patients with acute coronary syndrome and/or percutaneous coronary intervention. However, the delayed onset of the effect and the occurrence of poor platelet inhibition responders with clopidogrel as well as non-compliance to dual antiplatelet treatment are associated with a raised risk of stent thrombosis. The molecular target of the active metabolite of clopidogrel and several emerging antiplatelet treatments is the P2Y(12) receptor, which is the main platelet receptor responsible for ADP-induced platelet aggregation. Active metabolites of the thienopyridine prodrugs (ticlopidine, clopidogrel, and prasugrel) covalently bind to the P2Y(12) receptor and are irreversible, indirect platelet inhibitors. The newer, direct-acting P2Y(12) inhibitors (cangrelor and ticagrelor) change the conformation of the P2Y(12) receptor, resulting in reversible, concentration dependent inhibition of the receptor. An understanding of the similarities and differences in the properties and mechanisms of action of these new inhibitors compared with clopidogrel is needed in order to optimize the development and use of these agents in clinical practice. The objectives of this systematic review are to summarize the pharmacokinetics, pharmacodynamics, and pharmacogenetics of the different P2Y(12) inhibitors and to discuss the clinical implications for treatment of patients.

Topics: Acute Coronary Syndrome; Clopidogrel; Cytochrome P-450 Enzyme System; Humans; Piperazines; Platelet Aggregation Inhibitors; Polymorphism, Genetic; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Pyridines; Thiophenes; Ticlopidine

Proton-pump inhibitors (PPIs) are often prescribed in combination with thienopyridines. Conflicting data exist as to whether PPIs diminish the efficacy of clopidogrel. We assessed the association between PPI use, measures of platelet function, and clinical outcomes for patients treated with clopidogrel or prasugrel.. In the PRINCIPLE-TIMI 44 trial, the primary outcome was inhibition of platelet aggregation at 6 h assessed by light-transmission aggregometry. In the TRITON-TIMI 38 trial, the primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke. In both studies, PPI use was at physician's discretion. We used a multivariable Cox model with propensity score to assess the association of PPI use with clinical outcomes.. In the PRINCIPLE-TIMI 44 trial, 201 patients undergoing elective percutaneous coronary intervention were randomly assigned to prasugrel (n=102) or high-dose clopidogrel (n=99). Mean inhibition of platelet aggregation was significantly lower for patients on a PPI than for those not on a PPI at 6 h after a 600 mg clopidogrel loading dose (23.2+/-19.5% vs 35.2+/-20.9%, p=0.02), whereas a more modest difference was seen with and without a PPI after a 60 mg loading dose of prasugrel (69.6+/-13.5% vs 76.7+/-12.4%, p=0.054). In the TRITON-TIMI 38 trial, 13,608 patients with an acute coronary syndrome were randomly assigned to prasugrel (n=6813) or clopidogrel (n=6795). In this study, 33% (n=4529) of patients were on a PPI at randomisation. No association existed between PPI use and risk of the primary endpoint for patients treated with clopidogrel (adjusted hazard ratio [HR] 0.94, 95% CI 0.80-1.11) or prasugrel (1.00, 0.84-1.20).. The current findings do not support the need to avoid concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel or prasugrel.. Daiichi Sankyo Company Limited and Eli Lilly and Company sponsored the trials. This analysis had no funding.

Topics: Acute Coronary Syndrome; Aged; Cardiovascular Diseases; Clopidogrel; Drug Interactions; Drug Therapy, Combination; Female; Humans; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Multivariate Analysis; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Proportional Hazards Models; Proton Pump Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Risk Factors; Thiophenes; Ticlopidine; Treatment Outcome

Platelets play a central role in the atherosclerotic inflammatory response, thrombotic vascular occlusion, microembolization, vasoconstriction, and plaque progression. Persistent platelet activation poses a serious problem among patients with acute coronary syndromes (ACS) and those who have undergone percutaneous coronary intervention (PCI), placing them at risk for ischemic events and subacute stent thrombosis. Patients undergoing PCI are at risk for further ischemic events because of procedure-related platelet activation as well as the inherent persistent platelet hyperreactivity and enhanced thrombin generation associated with ACS. Persistent platelet activation following an acute coronary event and/or PCI supports incorporating antiplatelet strategies into the standard medical management of such patients. In this clinical setting, antiplatelet therapies are capable of improving outcomes. Aspirin, thienopyridines, and glycoprotein IIb/IIIa inhibitors, the 3 major pharmacologic approaches to persistent platelet activation, target various levels of the hemostatic pathways and thrombus formation.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Aspirin; Humans; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyridines; Thrombosis

Antiplatelet therapy is the cornerstone of treatment for patients with an acute coronary syndrome (ACS). However, patients presenting with possible ACS are a heterogeneous population, and there is a choice of many potential combination antiplatelet therapies, with aspirin, thienopyridines (eg, clopidogrel), and glycoprotein (GP) IIb/IIIa antagonists. The ISAR-REACT-2 trial investigated the optimal application of triple (aspirin 1 thienopyridine 1 GP IIb/IIIa inhibitor) versus dual (aspirin 1 thienopyridine) antiplatelet therapy for patients with ACS undergoing percutaneous coronary intervention. Abciximab was associated with a significant 25% relative reduction in risk for the 30-day combined endpoint of death, myocardial infarction, or urgent target vessel revascularization. All of this benefit was confined to the patients with elevated troponin levels. The data indicate that troponin can be used as a biomarker to identify patients most likely to benefit from the addition of a GP IIb/IIIa antagonist.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Aspirin; Biomarkers; Blood Platelets; Combined Modality Therapy; Drug Therapy, Combination; Humans; Myocardial Infarction; Patient Selection; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyridines; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Treatment Outcome; Troponin; Up-Regulation

Vorapaxar is effective in the prevention of secondary atherothrombotic events, although the efficacy/safety balance appears less favorable in the treatment of patients with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS). We hypothesized that patients with NSTE ACS already receiving thienopyridine prior to the ACS event may show differential efficacy/safety effects with vorapaxar vs. placebo added to their standard care.. We studied 12,944 patients from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial with respect to thienopyridine use before admission for the index NSTE ACS event. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, rehospitalization for ischemia, and urgent revascularization. The key secondary endpoint was a composite of cardiovascular death, myocardial infarction, and stroke. Safety endpoints were bleeding complications.. TRACER was largely conducted in thienopyridine-naïve patients with unknown tolerance to multiple antiplatelet treatments. Patients receiving thienopyridine before the index event may have had an attenuated increase in bleeding when adding vorapaxar, whereas concomitantly adding vorapaxar and thienopyridine in naïve patients may have uncovered a latent susceptibility to bleeding.

Topics: Acute Coronary Syndrome; Aged; Female; Hemorrhage; Humans; Lactones; Male; Middle Aged; Platelet Aggregation Inhibitors; Pyridines; Secondary Prevention; Treatment Outcome

Vorapaxar is an antagonist of the protease activated receptor-1 (PAR-1), the principal platelet thrombin receptor. The Thrombin Receptor Antagonist for Clinical Event Reduction (TRACER) trial evaluated vorapaxar compared to placebo in non-ST-elevation (NSTE)-acute coronary syndrome (ACS) patients. It was the study's objective to assess the pharmacodynamic effects of vorapaxar versus placebo that included aspirin or a thienopyridine or, frequently, a combination of both agents in NSTE-ACS patients. In a substudy involving 249 patients, platelet aggregation was assessed by light transmittance aggregometry (LTA) in 85 subjects (41 placebo, 44 vorapaxar) using the agonists thrombin receptor activating peptide (TRAP, 15 μM), adenosine diphosphate (ADP, 20 μM), and the combination of collagen-related peptide (2.5 μg/ml) + ADP (5 μM) + TRAP (15 μM) (CAT). VerifyNow® IIb/IIIa and vasodilator-stimulated phosphoprotein (VASP) phosphorylation assays were performed, and platelet PAR-1 expression, plasma platelet/endothelial and inflammatory biomarkers were determined before and during treatment. LTA responses to TRAP and CAT and VerifyNow results were markedly inhibited by vorapaxar. Maximal LTA response to TRAP (median, interquartile range) 2 hours post loading dose: placebo 68% (53-75%) and vorapaxar 3% (2-6%), p<0.0001. ADP inhibition was greater in the vorapaxar group at 4 hours and one month (p<0.01). In contrast to the placebo group, PAR-1 receptor number in the vorapaxar group at one month was significantly lower than the baseline (179 vs 225; p=0.004). There were significant changes in selected biomarker levels between the two treatment groups. In conclusion, vorapaxar caused a potent inhibition of PAR-1-mediated platelet aggregation. Further studies are needed to explore vorapaxar effect on P2Y12 inhibition, PAR-1 expression and biomarkers and its contribution to clinical outcomes.

Topics: Acute Coronary Syndrome; Adenosine Diphosphate; Aged; Aspirin; Biomarkers; Blood Platelets; Cells, Cultured; Europe; Female; Follow-Up Studies; Humans; Inflammation Mediators; Lactones; Male; Middle Aged; North America; Platelet Aggregation; Pyridines; Receptor, PAR-1; Receptors, Thrombin

The optimal duration of dual antiplatelet therapy (DAPT) after acute coronary syndrome (ACS) is not known. Factors influencing DAPT duration are not well described.. We hypothesized that continued DAPT 12 months beyond ACS would be associated with patient factors such as stent type and that it may be associated with lower rates of ischemic events.. The TIMI 38 Coronary Stent Registry (CSR) followed patients who completed the TRITON-TIMI 38 trial, received a stent, and were alive and event free. Continuation of DAPT was determined by the treating physician.. The CSR enrolled 2110 patients (1679>12 months from index ACS) and followed for a median of 2.1 additional years. DAPT was continued in 554 (26%) and was more likely to be continued in patients with drug-eluting stents (DES; 54%) and in North America. The rate of cardiovascular death, MI, or stroke was 2.35% per year, and 13 patients (0.6%) experienced Academic Research Consortium definite or probable ST. Recurrent ischemic events were similar between patients who continued thienopyridine therapy and those who stopped at registry entry (P = 0.74 for cardiovascular death/MI/stroke; P = 0.72 for definite or probable ST). After propensity score adjustment, there was no significant difference in cardiovascular death/MI/stroke (P = 0.55) or bleeding (P = 0.51) with prolonged DAPT.. Patients stabilized for a year after ACS and stenting have low rates of ST relative to overall cardiovascular events. The decision to continue DAPT maybe associated with stent type (DES vs bare-metal stent) and region.

Topics: Acute Coronary Syndrome; Aged; Combined Modality Therapy; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Prospective Studies; Pyridines; Registries; Stents; Stroke; Survival Analysis; Treatment Outcome

The aim of this study was to determine if rivaroxaban is associated with a reduction in stent thrombosis among patients with acute coronary syndromes (ACS) in the ATLAS-ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51) trial.. Dual antiplatelet therapy (DAPT) has been the mainstay of efforts to prevent stent thrombosis. Because thrombin is a potent stimulant of platelet activation, we hypothesized that inhibition of thrombin generation via factor Xa inhibition may further reduce the risk of stent thrombosis.. The ATLAS-ACS 2 TIMI 51 study was a placebo-controlled trial that randomly assigned 15,526 patients with recent ACS to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months.. Among patients who had a stent placed before or at the time of the index event, rivaroxaban significantly reduced independently adjudicated Academic Research Consortium definite and probable stent thrombosis in the pooled (1.9% vs. 1.5%; hazard ratio [HR]: 0.65; p = 0.017) and the 2.5 mg twice-daily (1.9% vs. 1.5%; HR: 0.61; p = 0.023) treatment groups when compared with placebo, with a trend toward a reduction in the 5 mg twice-daily treatment group (1.9% vs. 1.5%; HR: 0.70; p = 0.089). Among patients who received both aspirin and a thienopyridine (stratum 2), the benefit of rivaroxaban emerged during the period of active treatment with DAPT (HR: 0.68; 95% CI: 0.50 to 0.92, combined rivaroxaban group vs. placebo). Among stented patients who were treated with dual antiplatelet therapy, there was a mortality reduction among those treated with twice-daily rivaroxaban 2.5 mg (HR: 0.56; 95% CI: 0.35 to 0.89; p = 0.014).. Among stented patients with ACS treated with DAPT, the administration of twice-daily rivaroxaban 2.5 mg was associated with a reduction in stent thrombosis and mortality. (An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome; NCT00809965).

Topics: Acute Coronary Syndrome; Aged; Aspirin; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Morpholines; Platelet Aggregation Inhibitors; Pyridines; Rivaroxaban; Stents; Thiophenes; Thrombosis; Treatment Outcome

Prasugrel was associated with a statistically significant reduction in rates of cardiac ischemic events in patients with ACS who had undergone PCI. Rates of post-PCI death from cardiovascular causes, nonfatal MI, or nonfatal stroke were also significantly reduced with the use of prasugrel versus clopidogrel. Major bleeding was significantly increased with the use of prasugrel versus clopidogrel. Mortality did not differ significantly between the groups.

Topics: Acute Coronary Syndrome; Aspirin; Clopidogrel; Confidence Intervals; Double-Blind Method; Drug Therapy, Combination; Humans; Myocardial Ischemia; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Thiophenes; Ticlopidine

Rivaroxaban is an oral direct factor Xa inhibitor that has been effective in prevention of venous thromboembolism in patients undergoing elective orthopaedic surgery. However, its use after acute coronary syndromes has not been investigated. In this setting, we assessed the safety and efficacy of rivaroxaban and aimed to select the most favourable dose and dosing regimen.. In this double-blind, dose-escalation, phase II study, undertaken at 297 sites in 27 countries, 3491 patients stabilised after an acute coronary syndrome were stratified on the basis of investigator decision to use aspirin only (stratum 1, n=761) or aspirin plus a thienopyridine (stratum 2, n=2730). Participants were randomised within each strata and dose tier with a block randomisation method at 1:1:1 to receive either placebo or rivaroxaban (at doses 5-20 mg) given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor, or requiring medical attention); the primary efficacy endpoint was death, myocardial infarction, stroke, or severe recurrent ischaemia requiring revascularisation during 6 months. Safety analyses included all participants who received at least one dose of study drug; efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00402597.. Three patients in stratum 1 and 26 in stratum 2 never received the study drug. The risk of clinically significant bleeding with rivaroxaban versus placebo increased in a dose-dependent manner (hazard ratios [HRs] 2.21 [95% CI 1.25-3.91] for 5 mg, 3.35 [2.31-4.87] for 10 mg, 3.60 [2.32-5.58] for 15 mg, and 5.06 [3.45-7.42] for 20 mg doses; p<0.0001). Rates of the primary efficacy endpoint were 5.6% (126/2331) for rivaroxaban versus 7.0% (79/1160) for placebo (HR 0.79 [0.60-1.05], p=0.10). Rivaroxaban reduced the main secondary efficacy endpoint of death, myocardial infarction, or stroke compared with placebo (87/2331 [3.9%] vs 62/1160 [5.5%]; HR 0.69, [95% CI 0.50-0.96], p=0.0270). The most common adverse event in both groups was chest pain (248/2309 [10.7%] vs 118/1153 [10.2%]).. The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway.. Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare AG.

Topics: Acute Coronary Syndrome; Administration, Oral; Aspirin; Chest Pain; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Morpholines; Myocardial Infarction; Proportional Hazards Models; Pyridines; Recurrence; Risk Reduction Behavior; Rivaroxaban; Safety; Statistics, Nonparametric; Stroke; Thiophenes; Treatment Outcome

This study sought to evaluate the relative safety and efficacy of fondaparinux and enoxaparin in patients with acute coronary syndromes (ACS) treated with glycoprotein (GP) IIb/IIIa inhibitors or thienopyridines.. The OASIS 5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) trial showed that fondaparinux reduced major bleeding by 50% compared with enoxaparin while preserving similar efficacy. Whether this benefit is consistent in the presence or absence of concurrent antiplatelet therapy with clopidogrel and GP IIb/IIIa inhibitors is unknown.. Patients with ACS (n = 20,078) were randomized as a part of the OASIS 5 trial to receive either fondaparinux or enoxaparin. The use of GP IIb/IIIa inhibitors or thienopyridines was at the discretion of the treating physician. A Cox proportional hazard model was used to compare outcomes.. Of the 20,078 patients randomized, 3,630 patients received GP IIb/IIIa and 13,531 received thienopyridines. There was a 40% reduction in major bleeding with fondaparinux compared with enoxaparin in those treated with GP IIb/IIIa (5.2% vs. 8.3%, hazard ratio [HR]: 0.61, p < 0.001). A similar reduction was found in those treated with thienopyridines (3.4% vs. 5.4%, HR: 0.62, p < 0.001). Ischemic events were similar between the groups, resulting in a superior net clinical outcome (death, myocardial infarction, refractory ischemia, or major bleeding) favoring fondaparinux (GP IIb/IIIa subgroup 14.8% vs. 18.9%, HR: 0.77, p = 0.001 and thienopyridines subgroup 11.0% vs. 13.2%, HR: 0.82, p < 0.001).. In patients receiving GP IIb/IIIa inhibitors or thienopyridines, fondaparinux reduces major bleeding and improves net clinical outcome compared with enoxaparin.

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Drug Therapy, Combination; Enoxaparin; Female; Fondaparinux; Humans; Male; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Polysaccharides; Pyridines; Treatment Outcome

A 5- to 7-day washout period before coronary artery bypass grafting (CABG) is recommended for patients who have recently received a thienopyridine derivative; however, data supporting this guideline recommendation are lacking in Japanese patients.. Urgent isolated CABG was performed in 130 consecutive patients with acute coronary syndromes (ACS) (101 men; mean age, 69 years). Urgent CABG was defined as operation performed within 5 days after coronary angiography. All patients continued to receive aspirin 100mg/day. The subjects were retrospectively divided into 2 groups: 30 patients with preoperative thienopyridine (clopidogrel in 15 patients, ticlopidine in 15) exposure within 5 days [dual antiplatelet therapy (DAPT) group] and 100 patients without exposure [single antiplatelet therapy (SAPT) group].. Although the DAPT group had a higher proportion of patients who received perioperative platelet transfusions than the SAPT group (50% vs. 18%, p<0.001), intraoperative bleeding (median, 1100ml; interquartile range, 620-1440 vs. 920ml; 500-1100) and total drain output within 48h after surgery (577±262 vs. 543±277ml) were similar. CABG-related major bleeding, which was defined as type 4 or 5 bleeding according to the Bleeding Academic Research Consortium definitions, occurred in a significantly higher proportion of patients in the DAPT group than in the SAPT group (20% vs. 3%, p=0.005). This difference in major bleeding was driven mainly by the higher rate of transfusion of ≥5U red blood cells within a 48-h period in the DAPT group (13% vs. 1%, p=0.01). There was no significant difference in the 30-day composite endpoint including death, myocardial (re)infarction, ischemic stroke, and refractory angina between the DAPT group and SAPT group (17% vs. 19%).. Preoperative DAPT increases the risk of CABG-related major bleeding in Japanese patients with ACS undergoing urgent CABG.

Topics: Acute Coronary Syndrome; Aged; Aspirin; Blood Transfusion; Clopidogrel; Coronary Angiography; Coronary Artery Bypass; Emergencies; Female; Humans; Japan; Male; Middle Aged; Platelet Aggregation Inhibitors; Postoperative Hemorrhage; Preoperative Care; Pyridines; Retrospective Studies; Ticlopidine; Time Factors; Treatment Outcome

This article outlines a new hypothesis that illustrates the potential role of the stomach (and subsequent chemical reactions involving nitrite therein) in modifying thienopyridines, such as clopidogrel. Gastric modification of thienopyridines can occur before standard accepted biotransformation pathways ensue. We hypothesised that thienopyridines expose the free thiol group once acidified (by the stomach) before biotransformation into active metabolites, and in the presence of nitrite (from saliva and the stomach) to form nitrosothiol derivatives (Thienopyridine induced-SNO formation). We have performed in vitro studies with each of the thienopyridines tablets/compounds confirming direct Th-SNO formation from the parent (inactive) drug by the following mechanism. Thienopyridine-SH + H(+ (Stomach)) +  [Formula: see text] ↔ Thienopyridine-SNO + H2O Thienopyridine-SNO (an S-nitrosothiol molecule) would have the potential to participate in all the reactions expected of native nitric oxide (NO) with added benefit that the NO "moiety" is protected, transportable and largely preserved from further reactive metabolism. All these biochemical steps are present in humans and could occur prior to enzymatic biotransformation.

Topics: Acute Coronary Syndrome; Blood Platelets; Clopidogrel; Gastric Mucosa; Humans; Hydrogen-Ion Concentration; Models, Biological; Nitrates; Nitric Oxide; Nitrogen; Oxygen; Platelet Aggregation Inhibitors; Pyridines; Receptors, Purinergic P2Y12; S-Nitrosothiols; Sulfhydryl Compounds; Ticlopidine

Topics: Acute Coronary Syndrome; Blood Platelets; Humans; Platelet Aggregation Inhibitors; Platelet Function Tests; Practice Guidelines as Topic; Pyridines

High residual platelet aggregability during thienopyridine treatment occurs because of low levels of the active drug metabolite, and is associated with an increased rate of major adverse cardiovascular events. Recent findings suggest that paraoxonase-1 (PON1) is a major determinant for clopidogrel efficacy. The aim of this study was to assess the impact of serum PON1 activity on platelet aggregability in thienopyridine-treated patients. In 72 patients receiving treatment with aspirin and ticlopidine after acute coronary syndrome, various laboratory data including the formation of platelet aggregations induced by agonists were compared with serum PON1 activities, measured as paraoxonase and homocysteine thiolactone hydrolase (HTLase). Serum paraoxonase activity was significantly associated with HTLase activity (R=0.4487, P<0.0001). These PON1 activities were not correlated with any parameters for platelet aggregation, hypertension, sleep apnea, and diabetes mellitus. In contrast, serum PON1 activities seemed to be involved in cardiac function, with brain natriuretic peptide and ejection fraction being significantly correlated with serum HTLase activity (R=-0.2767, P=0.0214) and paraoxonase activity (R=0.2558, P=0.0339), respectively. Paraoxonase activity also demonstrated a significant association with increased levels of ankle-brachial index (R=0.267, P=0.0255). Serum PON1 activities did not influence platelet aggregability during treatment with thienopyridine. However, they might modulate cardiac function after acute coronary syndrome and progression of atherosclerosis.

Topics: Acute Coronary Syndrome; Aryldialkylphosphatase; Enzyme Activation; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Pyridines; Statistics as Topic; Treatment Outcome

We sought to identify patients at risk for premature discontinuation of thienopyridines and to develop a risk score for thienopyridine adherence after coronary stent implantation. Patients were prospectively included from December 2007 to March 2008. At 1-month follow-up, all patients were given the Morisky questionnaire and asked if they had stopped taking thienopyridines. Multivariate analysis identified predictors of thienopyridine discontinuation; points were assigned to each variable according to the odds ratios and the c-statistic of the score was calculated. Mean age of the 400 patients included was 61.0 ± 10.4 years; 66 patients (16.5%) stopped thienopyridines after 1 month. Reasons for discontinuation were cost (62%), lack of information (17%), and recommendation by another doctor to stop treatment (15%). Factors associated with discontinuation included unmarried status (odds ratio 2.48, p = 0.046), lack of private health insurance (odds ratio 4.68, p = 0.041), acute coronary syndrome (odds ratio 2.31, p = 0.004), nondiabetics (odds ratio 2.20, p = 0.041), and patients who earned <2 times (odds ratio 8.23, p <0.001) and 2 to 3 times (odds ratio 4.46, p = 0.021) the minimum wage. Total risk score was 0 to 14 points and was strongly associated with thienopyridine discontinuation. For total scores of 0 to 4, 5 to 8, 9 to 12, and ≥13, 0%, 7%, 20%, and 37% of patients, respectively, stopped thienopyridines (c-statistic 0.76, p <0.0001). Risk score was also significantly associated with complete adherence as assessed by the Morisky questionnaire (c-statistic 0.74, p <0.001). In conclusion, we have identified patients at risk for premature discontinuation of thienopyridines using variables obtained before stent implantation and developed a risk score that accurately predicts premature thienopyridine discontinuation.

Topics: Acute Coronary Syndrome; Brazil; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Patient Compliance; Postoperative Care; Prospective Studies; Pyridines; Risk Assessment; Risk Factors; Stents; Surveys and Questionnaires; Treatment Refusal

This study sought to assess the cost-effectiveness of bivalirudin versus heparin plus glycoprotein IIb/IIIa inhibitor (GPI) in thienopyridine-treated non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients undergoing early or urgent invasive management, from a United Kingdom National Health Service perspective.. A decision-analytic model with lifelong time horizon was populated with event risks and resource use parameters derived from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial raw data. In a parallel analysis, key comparator strategy inputs came from Global Registry of Acute Coronary Events (GRACE) patients enrolled in the United Kingdom. Upstream and catheter laboratory-initiated GPI were assumed to be tirofiban and abciximab, respectively. Life expectancy of first-year survivors, unit costs, and health-state utilities came from United Kingdom sources. Costs and effects were discounted at 3.5%. Incremental cost-effectiveness ratios (ICERs) were expressed as cost per quality-adjusted life year (QALY) gained.. Higher acquisition costs for bivalirudin were partially offset by lower hospitalization and bleeding costs. In the ACUITY-based analysis, per-patient lifetime costs in the bivalirudin and heparin plus GPI strategies were £10,903 and £10,653, respectively. Patients survived 10.87 and 10.82 years on average, corresponding to 5.96 and 5.93 QALYs and resulting in an ICER of £9,906 per QALY gained. The GRACE-based ICER was £12,276 per QALY gained. In probabilistic sensitivity analysis, 72.1% and 67.0% of simulation results were more cost-effective than £20,000 per QALY gained, in the ACUITY-based and GRACE-based analyses, respectively. Additional scenario analyses implied that greater cost-effectiveness may be achieved in actual clinical practice.. Treating NSTE-ACS patients undergoing invasive management with bivalirudin is likely to represent a cost-effective option for the United Kingdom, when compared with the current practice of using heparin and a GPI.

Topics: Abciximab; Acute Coronary Syndrome; Antibodies, Monoclonal; Anticoagulants; Cost-Benefit Analysis; Decision Trees; Drug Therapy, Combination; Female; Health Care Costs; Heparin; Hirudins; Humans; Immunoglobulin Fab Fragments; Male; Middle Aged; Models, Econometric; Myocardial Revascularization; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Pyridines; Quality-Adjusted Life Years; Recombinant Proteins; Survival Analysis; Tirofiban; Tyrosine; United Kingdom

The standard antithrombotic therapy for treatment of patients with acute coronary syndrome (ACS) is dual antiplatelet therapy with aspirin and clopidogrel (Plavix) or another thienopyridine, plus a parenteral anticoagulant while the patient is hospitalized, followed by antiplatelet therapy alone after discharge. The addition of the oral anticoagulant warfarin (Coumadin, and others) to dual antiplatelet therapy is generally not recommended for this indication because of fluctuations in its anticoagulant effect and the risk of bleeding. A recently published trial found that addition of a low dose of the oral anticoagulant rivaroxaban (Xarelto) to antiplatelet therapy after discharge reduced the risk of major cardiovascular events without increasing the incidence of fatal bleeding.

Topics: Acute Coronary Syndrome; Anticoagulants; Aspirin; Dose-Response Relationship, Drug; Drug Approval; Drug Therapy, Combination; Factor Xa Inhibitors; Humans; Morpholines; Pyridines; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes; United States; United States Food and Drug Administration

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Clopidogrel; Drug Interactions; Humans; Platelet Aggregation Inhibitors; Proton Pump Inhibitors; Pyridines; Selection Bias; Ticlopidine

Topics: Acute Coronary Syndrome; Aspirin; Clopidogrel; Drug Therapy, Combination; Drug-Eluting Stents; Electrocardiography; Follow-Up Studies; Gastrointestinal Hemorrhage; Humans; Myocardial Infarction; Myocardial Revascularization; Odds Ratio; Peptic Ulcer; Platelet Aggregation Inhibitors; Prognosis; Proton Pump Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Ticlopidine; Time Factors

Antithrombotic and antiplatelet therapies have been proposed to treat non-ST elevation acute coronary syndrome (NSTEACS), yet limited information is available about their applications from a multicenter "real-world" clinical procedure, especially in China. This study was undertaken to characterize the use of antithrombotic and antiplatelet agents in relation to the risk levels of the NSTEACS patients who were enrolled in Sino-Global Registry of Acute Coronary Events (GRACEs) registry study.. We analyzed the data from 618 Chinese NSTEACS patients stratified into low-(n = 151), intermediate-(n = 233), and high-risk groups (n = 234) based on GRACE risk scores. The baseline characteristics, clinical presentations, antithrombotic and antiplatelet agents were recorded and compared among the three groups.. The administration rates of low-molecular-weight heparins (LMWHs) (86.08%) and thienopyridines (85.92%) were higher whereas the administration rate of glycoprotein IIb/IIIa inhibitor (1.78%) was much lower than those reported previously. Meanwhile, within the first 24 hours of admission, the use of heparin/LMWHs in the high-risk group was more than that in the intermediate- and low-risk groups (73.50% vs 63.09% vs 55.63%, P = 0.001). Furthermore, the combination of antithrombotic and antiplatelet medications showed no significant differences in all groups.. In the "real world" practice of China, the antithrombotic and antiplatelet therapies on NSTEACS are well adherent to the current guidelines except for several gaps, such as the very low use of glycoprotein IIb/IIIa inhibitor. Moreover, these antithrombotic and antiplatelet treatments usually tend to be underused for the high-risk ones.

Topics: Acute Coronary Syndrome; Aged; Coronary Disease; Female; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyridines; Registries; Risk Assessment

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Clopidogrel; Drug Interactions; Gastrointestinal Hemorrhage; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Proton Pump Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Thiophenes; Ticlopidine

The benefits and limitations of current antiplatelet therapies in the management of patients experiencing acute coronary syndrome (ACS) are reviewed.. Antiplatelet agents, including aspirin, thienopyridines, and platelet glycoprotein (GP) IIb/IIIa receptor inhibitors, have become the foundation of antithrombotic therapy in the management of patients experiencing ACS. Despite aspirin's ability to reduce the risk for adverse thrombotic events in a broad range of patients, it has variable antiplatelet activity in individual patients. The term "aspirin resistance" describes the inability of aspirin to produce an anticipated effect on one or more tests of platelet function. Because a substantial proportion of patients are "resistant" to the antiplatelet effects of aspirin, and other pathways for platelet aggregation are not inhibited by aspirin, current guidelines recommend a dual antiplatelet regimen with a thienopyridine or GP IIb/IIIa inhibitor in addition to aspirin for patients with ACS, including patients undergoing percutaneous coronary intervention and stent placement. These guidelines are based on observational and randomized clinical trials supporting the effectiveness of dual antiplatelet therapy in reducing mortality, nonfatal myocardial infarction, and the need for urgent revascularization compared with placebo, aspirin therapy alone, or an anticoagulant regimen. Studies in small numbers of patients have also revealed that some patients may be resistant to a thienopyridine, with some suggestion of a genetic etiology. Additional studies are needed to provide more definitive answers.. Improved awareness by healthcare professionals of the benefits and limitations of various antiplatelet therapies should aid in the development of strategies to ensure patient compliance and thereby reduce the morbidity and mortality associated with premature discontinuation of dual antiplatelet therapy.

Topics: Acute Coronary Syndrome; Aspirin; Clinical Protocols; Drug Therapy; Fibrinolytic Agents; Humans; Platelet Aggregation Inhibitors; Pyridines; Risk Factors; Stents