ticagrelor and Thrombosis

Limited data comparing prasugrel and ticagrelor in acute coronary syndrome are available. Online databases, including MEDLINE and Cochrane Central, were queried to compare these drugs. The primary outcomes of this meta-analysis are myocardial infarction (MI), all-cause mortality, cardiovascular mortality, noncardiovascular mortality, stent thrombosis, and stroke. The secondary outcome is major bleeding. A total of 9 studies, including 94,590 patients (prasugrel group = 32,759; ticagrelor group = 61,831), were included in this meta-analysis. The overall mean age was 62.73 years, whereas the mean age for the ticagrelor and prasugrel groups was 63.80 and 61.65 years, respectively. Prasugrel is equally effective as compared with ticagrelor in preventing MI. There was no difference between the 2 groups regarding all-cause mortality, stent thrombosis, stroke, or major bleeding. In patients with acute coronary syndrome, prasugrel is equally effective when compared with ticagrelor in preventing MI.

Topics: Acute Coronary Syndrome; Hemorrhage; Humans; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Stroke; Thrombosis; Ticagrelor; Treatment Outcome

The risk of bleeding is high in East Asians, whether East Asian patients with acute coronary syndrome choose ticagrelor or clopidogrel is still controversial. In this study, PubMed, EMBASE, Cochrane Library database, and other sources were systematically searched. The primary efficacy outcome was all-cause death, the primary safety outcomes were any bleeding, PLATO major bleeding, and fatal bleeding. The secondary outcomes included vascular-cause death, myocardial infarction, stent thrombosis, stroke, and dyspnea. A total of 8 randomized controlled trials with 3597 patients met inclusion criteria. Compared with clopidogrel, ticagrelor had significantly higher incidence of any bleeding [risk ratio (RR), 1.63; 1.33-1.99; P < 0.00001], PLATO major bleeding (RR 1.56; 1.15-2.12; P = 0.004), and dyspnea (RR 2.60; 1.68-4.00; P < 0.00001). However, ticagrelor was associated with a significantly reduced risk of stent thrombosis (RR 0.42; 0.19-0.92; P = 0.03). There was no significant difference in the risk of all-cause death (RR 0.87; 0.64-1.24; P = 0.44), fatal bleeding (RR 2.49; 0.79-7.86; P = 0.12), vascular-cause death (RR 0.88; 1.60-0.30; P = 0.52), myocardial infarction (RR 0.89; 0.65-1.23; P = 0.49), and stroke (RR 0.84; 0.47-1.50; P = 0.56) between the 2 groups. The present findings demonstrated that ticagrelor was associated with a higher risk of any bleeding, PLATO major bleeding, and dyspnea compared with clopidogrel in East Asian patients with acute coronary syndrome. However, it significantly reduced the risk of stent thrombosis. (Registered by PROSPERO, CRD42021255215).

Topics: Acute Coronary Syndrome; Asian People; Clopidogrel; Dyspnea; Hemorrhage; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Stroke; Thrombosis; Ticagrelor; Treatment Outcome

The efficacy and safety of clopidogrel compared with ticagrelor as part of dual antiplatelet therapy in patients, and in older patients, with acute coronary syndrome is reviewed. PubMed, Embase, the Cochrane Library, MEDLINE, and HTA databases were searched (September 2, 2020) for randomized controlled trials (RCTs). Pooled risk differences (clopidogrel minus ticagrelor) were estimated using random-effects meta-analyses, and certainty of evidence was assessed according to Grading of Recommendations Assessment, Development, and Evaluation. In all, 29 RCTs were identified. The risk difference for all-cause mortality was 0.6% (-0.03% to 1.3%), cardiovascular (CV) mortality: 0.6% (95% confidence interval: 0.01% to 1.1%), myocardial infarction (MI): 0.9% (0.4% to 1.3%), stent thrombosis: 0.7% (0.4 to 1.1%), clinically significant bleeding: -1.9% (-3.7% to -0.2%), major bleeding: -0.9% (-1.6% to -0.1%), and dyspnea: -5.8% (-7.7% to -3.8%). In older patients, there were no differences between the comparison groups regarding all-cause mortality, CV mortality, and MI, whereas the risk of clinically significant bleeding and major bleeding was lower in the clopidogrel group, -5.9% (-11 to -0.9%, 1 RCT) and -2.4% (-4.4% to -0.3%), respectively. Compared with ticagrelor, clopidogrel may result in little or no difference regarding all-cause mortality. Although not evident in older patients, it cannot be excluded that clopidogrel may be slightly less efficient in reducing the risk of CV mortality and MI, whereas ticagrelor is probably more efficacious in reducing the risk of stent thrombosis. Clopidogrel results in a reduced risk of dyspnea and clinically significant bleeding and in older people probably in a reduced risk of major bleeding.

Topics: Acute Coronary Syndrome; Aged; Clopidogrel; Dyspnea; Hemorrhage; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Thrombosis; Ticagrelor; Treatment Outcome

P2Y12 inhibitors, including aspirin, are key components of dual-antiplatelet therapy (DAPT), which is the optimal therapeutic strategy for preventing arterial thrombosis in patients with acute coronary syndromes (ACS) who underwent stent implantation. Ticagrelor is a cyclopentyl-triazole pyrimidine antiplatelet drug that was the first reversible oral P2Y12 receptor antagonist. Compared with clopidogrel, ticagrelor exerts a faster onset and offset of function by reversible and selective inhibition of platelet aggregation in ACS patients, including those with coronary artery blood revascularization. Despite improvement in stent materials, stent thrombosis (ST) due to high on-treatment platelet reactivity (HPR) to clopidogrel continues to occur. In addition to antiplatelet aggregation, ticagrelor displays pleiotropic cardioprotective effects, including improving coronary blood flow, reducing myocardial necrosis after an ischemic event, and anti-inflammatory effects. The benefits of ticagrelor over clopidogrel were consistent in the PLATO results, with lower incidence of the primary endpoint. Also, in 2020, the findings from the phase 3 THALES trial (NCT03354429) showed that aspirin combined with 90 mg of ticagrelor significantly reduced the rates of stroke and death compared with aspirin alone in patients with AIS or TIA. Here, we review recent research on the superiority of ticagrelor over clopidogrel, discuss the pharmacological mechanism, and present future perspectives. This review aims to present the roles of ticagrelor in the management of acute coronary syndrome, acute thrombotic disease, and other diseases.

Topics: Acute Coronary Syndrome; Aspirin; Clopidogrel; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Thrombosis; Ticagrelor

Clopidogrel, prasugrel and ticagrelor, acting on platelet P2Y12 receptor, are commonly used for prevention of stent thrombosis (ST) among patients who underwent percutaneous coronary intervention (PCI). This study aimed to compare the effects of these drugs by a systematic review and network meta-analysis.. Efficacies of clopidogrel, prasugrel and ticagrelor on preventing ST are not the same.. PubMed, Embase and Cochrane Library were searched for randomized controlled trials (RCTs) that investigated the effect of clopidogrel, prasugrel, or ticagrelor on prevention of ST in patients who underwent PCI. The efficacies between groups were compared by a Bayesian network meta-analysis, by which the pooled odds ratios (ORs) and 95% confidence intervals (CIs) was calculated.. Fourteen studies and 46 983 participants were included in this study. The pooled results illustrated that clopidogrel, prasugrel and ticagrelor were effective on prevention of ST. Patients treated with prasugrel (OR = 0.30, 95% CI = 0.052 ~ 0.73, P < 0.05) and ticagrelor (OR = 0.25, 95% CI = 0.035 ~ 0.65, P < 0.05) had lower incidence of ST compared to those treated with clopidogrel. Patients treated with ticagrelor showed similar frequency with those in prasugrel group (OR = 0.86, 95% CI = 0.22 ~ 2.3, P > 0.05). No significant heterogeneity was observed across included studies.. Our findings suggest that prasugrel and ticagrelor are more effective than clopidogrel on prevention of ST among patients underwent PCI. Simultaneously, there is no significant difference in the prevention of ST between prasugrel and ticagrelor.

Topics: Clopidogrel; Humans; Network Meta-Analysis; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Stents; Thrombosis; Ticagrelor

Cardiovascular complications remain the main cause of mortality and morbidity in diabetes. This is related to advanced vascular pathology in this population, together with an enhanced thrombotic environment. The increased risk in thrombosis is secondary to platelet hyper-reactivity and increased levels and/or altered activity of coagulation factors. The current review is focused on the role of antiplatelet agents in modulating the thrombotic milieu in diabetes and improving vascular outcome in this high-risk population. We review the latest evidence for the use of aspirin in primary vascular prevention together with long-term treatment with this agent for secondary prevention. We also discuss the effects of the various P2Y

Topics: Aspirin; Cardiovascular Diseases; Clopidogrel; Diabetes Mellitus; Humans; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Primary Prevention; Secondary Prevention; Thrombosis; Ticagrelor

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y. A search of PubMed was performed to identify articles published in the last 20 years that addressed the role of DAPT beyond 12 months' duration.. A number of studies have shown ischemic benefits associated with prolonging DAPT beyond 12 months, but this finding is dependent on the patient population studied and the quality of the study design. Many studies also show that longer duration therapy has been associated with increased bleeding risk. In patients with previous myocardial infarction completing at least 1 year of DAPT, continuing DAPT with a reduced dose of ticagrelor 60 mg BID is a regimen to be considered for these patients; in general ACS patients, a reduced dose of 60 mg BID of ticagrelor after the first year of DAPT should be considered; and in the post-percutaneous coronary intervention patients, DAPT beyond 1 year should be considered after careful evaluation of the patient's thrombotic and bleeding risks.. The duration of DAPT, and the choice of P2Y

Topics: Acute Coronary Syndrome; Aspirin; Drug Therapy, Combination; Drug-Eluting Stents; Hemorrhage; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Risk Factors; Secondary Prevention; Thrombosis; Ticagrelor; Time Factors

There are clinical scenarios where the balance between the risk of ischemic and bleeding events leads to the clinical decision to reverse the antiplatelet effect of P2Y

Topics: Administration, Oral; Antibodies, Monoclonal; Blood Platelets; Broadly Neutralizing Antibodies; Cardiology; Clopidogrel; Hemadsorption; Hemorrhage; Hemostasis; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Risk; Signal Transduction; Thrombosis; Ticagrelor

To determine the therapeutic effects of pre-admission ticagrelor in acute ST elevation myocardial infarction after primary percutaneous coronary intervention.. The meta analysis was conducted at the period from the establishment of the database to the February 2018 period, and comprised earlier studies that were selected after comprehensive search of PubMed, Medline, Excerpta Medica dataBASE and Cochrane databases. The studies compared the pre-treatment group (pre-hospital ticagrelor) with the control group (in-hospital ticagrelor) and found differences in primary percutaneous coronary intervention outcomes for sick individuals suffering from acute ST elevation myocardial infarction.. The two studies selected together had 1915 subjects. The rate of stent thrombosis in the control group was higher than in the pre-treatment group (p<0.01), but there were no significant differences in all-cause mortality (p=0.88), myocardial infarction (p=0.17) and stroke (p=0.49).. Pre-hospital ticagrelor decreased the incidence of stent thrombosis in patients with acute ST elevation myocardial infarction who underwent primary percutaneous coronary intervention.

Topics: Emergency Medical Services; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prosthesis Failure; ST Elevation Myocardial Infarction; Stents; Thrombosis; Ticagrelor; Time-to-Treatment

More potent antithrombotic strategies have significantly reduced the rate of recurrent ischemic events in cardiovascular disease. Ticagrelor, in particular, has significantly improved the outcome in patients with acute coronary syndromes, offering potential benefits also in terms of survival. In addition, more recent data have suggested that the advantages of ticagrelor could be extended also to non-coronary atherothrombotic disease, although with contrasting results, especially for mortality reduction. The aim of the present meta-analysis was to investigate the safety and effectiveness of a newer antiplatelet strategy with ticagrelor as compared to traditional antiplatelet regimens in patients with coronary or non-coronary atherothrombotic disease.. Literature and main scientific session abstracts were searched for studies comparing a ticagrelor-based antiplatelet regimen vs. different antiplatelet agents in the secondary prevention of cardiac, cerebral or vascular atherothrombotic events. The primary efficacy endpoint was mortality, primary safety endpoint was the occurrence of major bleedings. Secondary endpoints were myocardial infarction and stroke.. We included 10 randomized clinical trials, for a total population of 73,121 patients, 54.9% randomized to ticagrelor. At a mean follow-up of 13.4 ± 12.6 months, a newer antiplatelet strategy based on ticagrelor was associated with a significant reduction in mortality as compared to a traditional therapy (OR[95%CI] = 0.92[0.86,0.99], p=0.02; phet = 0.14), however, such benefits were more evident in patients with coronary artery disease, while not in non-coronary trials, with a significant interaction between patients' setting and the prognostic impact of ticagrelor (p int = 0.03). A similar result was achieved for cardiovascular mortality, recurrent myocardial infarction, while for the risk of stroke, the largest advantages were observed in patients with a previous cerebrovascular accident. Major bleeding events were increased in ticagrelor treated patients (OR [95%CI] = 1.11 [1.02, 1.20], p=0.01; phet = 0.0003), although not affecting overall mortality, as confirmed by meta-regression analysis.. Based on the current meta-analysis, a newer antiplatelet strategy based on ticagrelor is associated with a significant reduction in mortality and recurrent cardiovascular events, as compared to a traditional treatment, among patients treated for coronary disease but not among those with non-coronary atherothrombotic disease. However, ticagrelor therapy was associated with a significant increase in major bleeding complications.

Topics: Atherosclerosis; Coronary Artery Disease; Coronary Thrombosis; Humans; Randomized Controlled Trials as Topic; Thrombosis; Ticagrelor

Carotid angioplasty and stenting (CAS) represents an effective procedure for treating carotid artery disease. The acute in-stent thrombosis is an extremely rare complication of CAS especially when it occurs postprocedurally during the first 24 hours. Improper antiplatelet therapy or poor response to antiplatelet medications is known to be associated with a higher risk of in-stent thrombosis during early postprocedural period following a successful intervention.. A patient who experienced acute carotid in-stent thrombosis in early postprocedural period is described. He had been taking dual antiplatelet therapy for 2 weeks before undergoing a successful CAS. Moreover, pharmacogenetics studies showed the patient to be a clopidogrel ultrarapid metabolizer, which theoretically confers hyperresponsivity to medication. Alongside the report itself, a brief literature review of relevant sources pertinent to the case has been conducted.. According to the available literature, this is the first case report describing an ultrarapid clopidogrel metabolizer who underwent an uneventful CAS but experienced acute carotid in-stent thrombosis in early postprocedural period. A rescue procedure included an endovascular intervention consisting of thrombectomy and local alteplase application, followed by postprocedural administration of intravenous eptifibatide. At discharge, patient's dual antiplatelet therapy included ticagrelor instead of clopidogrel.. Acute carotid in-stent thrombosis is a highly unexpected complication of CAS and can occur despite ultrarapid clopidogrel metabolism trait.

Topics: Acute Disease; Administration, Intravenous; Angiography, Digital Subtraction; Angioplasty, Balloon; Carotid Stenosis; Clopidogrel; Computed Tomography Angiography; Cytochrome P-450 CYP2C19; Drug Substitution; Eptifibatide; Genotype; Humans; Male; Middle Aged; Pharmacogenomic Variants; Phenotype; Platelet Aggregation Inhibitors; Risk Factors; Stents; Thrombectomy; Thrombosis; Ticagrelor; Treatment Outcome

The National Institute for Health and Care Excellence (NICE) invited AstraZeneca, the manufacturer of ticagrelor (Brilique

Topics: Aspirin; Cost-Benefit Analysis; Drug Therapy, Combination; England; Humans; Models, Economic; Myocardial Infarction; Platelet Aggregation Inhibitors; Quality-Adjusted Life Years; Secondary Prevention; Technology Assessment, Biomedical; Thrombosis; Ticagrelor; Wales

The introduction of ticagrelor, one of the first directly-acting oral antiplatelet drugs, provided new possibilities in the prevention of thrombotic events in patients with acute coronary syndromes (ACS). Current guidelines recommend ticagrelor in dual antiplatelet therapy with aspirin over clopidogrel for prevention of stent thrombosis in patients with ACS. Moreover, in the management of ACS, lipid-lowering treatment with high-intensity statin therapy is advised for secondary prevention of cardiovascular events over the long term. Despite the apparent advantages of combined antiplatelet and lipid-lowering treatments, a possible interaction between statins and ticagrelor may lead to myopathy and rhabdomyolysis. In this review, relevant information was gathered on the ticagrelor-statin interaction that might lead to this life-threatening condition. This review focuses on the most widely used statins-simvastatin, atorvastatin, and rosuvastatin. Possible mechanisms of this interaction are discussed, including CYP3A4 isoenzymes, organic anion transporter polypeptide (OATPs), P-glycoprotein and glucuronidation. PubMed database was searched for relevant case reports and all data gathered from the introduction of ticagrelor to March 2018 are presented and discussed. In summary, co-administration of statins and ticagrelor was found to be relatively safe in routinely prescribed doses. However, caution should be exercised, especially in elder populations.

Topics: Acute Coronary Syndrome; Drug Interactions; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscular Diseases; Platelet Aggregation Inhibitors; Rhabdomyolysis; Risk; Thrombosis; Ticagrelor

Although the rate of cardiovascular disease (CVD)-related mortality has declined over the last decade, it is still the leading cause of mortality in the USA, accounting for over 1.4 million deaths annually. In addition, total direct (primarily hospital admissions) and indirect costs of CVD in the US is over $316 billion annually and is expected to grow to over $918 billion by 2030. Much of the etiology of CVD is due to atherosclerosis and its thrombotic complications, and central to this is the role of platelets. Atherosclerosis is a systemic disease, with meaningful morbidity and mortality when present in the coronary, cerebral, or major peripheral arteries. The recommended antiplatelet therapy differs based on the vascular bed impacted, with the optimal antiplatelet therapy yet to be defined. The PARTHENON program is a series of completed and ongoing phase III clinical trials investigating the efficacy and safety of ticagrelor in atherosclerotic CVD in comparison with established antiplatelet therapy or placebo. The overall aim of the program is to determine if more potent antiplatelet therapy, with different pharmacology, may reduce cardiovascular events in patients with atherosclerotic disease.

Topics: Adenosine; Atherosclerosis; Cardiovascular Diseases; Humans; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Thrombosis; Ticagrelor

This review aims to summarize and discuss safety and effectiveness of the long-term use of ticagrelor in patients with coronary artery disease (CAD).. Ticagrelor is an orally administered, direct, and reversible inhibitor of the P2Y

Topics: Adenosine; Blood Platelets; Coronary Artery Disease; Hemorrhage; Humans; Myocardial Infarction; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Thrombosis; Ticagrelor; Treatment Outcome

Aspirin, the first antiplatelet agent, has been around since the 19th century, and is one of the most established drugs in history. With the improvement of coronary interventions in the past few decades, there has been more reliance on oral antiplatelet agents to reduce complications of in-stent restenosis/thrombosis. Clopidogrel was initially introduced in 1997, and within the past seven years, two additional oral antiplatelet agents have been approved by the U.S. Food and Drug Administration. With more potent antiplatelet agents comes increased risks of adverse effects. Physicians of all fields should be aware of the common antiplatelet agents used today, and the basic landmark trials that allowed them to be on the market today. The focus of this review article is to evaluate each oral antiplatelet drug, its brief history, relevant trials, indications and management of complications through evidence based guidelines.

Topics: Adenosine; Administration, Oral; Aspirin; Cardiovascular Diseases; Clopidogrel; Gastrointestinal Hemorrhage; Humans; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Risk Factors; Thrombosis; Ticagrelor; Ticlopidine

High on-clopidogrel platelet reactivity (HcPR) during dual-antiplatelet therapy is a marker of vascular risk, in particular stent thrombosis, in patients with acute coronary syndromes (ACS). Genetic determinants (CYP2C19*2 polymorphism), advanced age, female gender, diabetes and reduced ventricular function are related to a higher risk to develop HcPR. In addition, inflammation and increased platelet turnover, as revealed by the elevated percentage of reticulated platelets in patients' blood, that characterize the acute phase of acute coronary syndromes, are associated with HcPR. To overcome the limitation of clopidogrel, new antiplatelet agents (prasugrel and ticagrelor) were developed and the demonstration of their superiority over clopidogrel was obtained in the two randomized trials, TRITON TIMI 38 and PLATO. Emerging evidence is accumulating on the role of high-on aspirin platelet reactivity (HaPR), especially in the clinical context of diabetes. Finally, the presence of new, potent antiplatelet drugs has shifted the focus from thrombotic to bleeding risk. Recent data document that low on-treatment platelet reactivity (LPR) is associated with a significantly higher bleeding risk. Due to the current possibility to choose between multiple antiplatelet strategies, the future perspective is to include in the management of ACS, in addition to clinical data and classical risk factors, the definition of platelet function during treatment in order to set a tailored therapy.

Topics: Acute Coronary Syndrome; Adenosine; Age Factors; Blood Platelets; Clopidogrel; Cytochrome P-450 CYP2C19; Drug Interactions; Hemorrhage; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Polymorphism, Genetic; Prasugrel Hydrochloride; Sex Factors; Stents; Thrombosis; Ticagrelor; Ticlopidine

A P2Y

Topics: Acute Coronary Syndrome; Adenosine; Aspirin; Clopidogrel; Humans; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Thrombosis; Ticagrelor; Ticlopidine

Ticagrelor (Brilique™, Brilinta®), a cyclopentyl-triazolopyrimidine, is an orally active, reversible, and selective adenosine diphosphate (ADP) receptor antagonist indicated for use in patients with acute coronary syndromes (ACS). Ticagrelor has a faster onset of action and provides greater inhibition of platelet aggregation than clopidogrel. In the large well-designed, PLATO study in adult patients with ACS, 12 months' treatment with ticagrelor was more effective than clopidogrel in reducing the incidence of the primary composite endpoint of myocardial infarction, stroke, or cardiovascular (CV) death. Ticagrelor also reduced all-cause mortality relative to clopidogrel, although statistical significance of this was not confirmed in hierarchical testing. Benefit with ticagrelor was seen both in invasively and noninvasively managed patients. Ticagrelor was generally well tolerated and was not associated with an increased risk of major bleeding relative to clopidogrel. However, the incidences of non-coronary artery bypass grafting (CABG)-related bleeding, and major or minor bleeding, as well as some non-hemorrhagic adverse events, including dyspnea (usually of mild or moderate severity) and ventricular pauses (largely asymptomatic) were higher with ticagrelor. In addition, the ATLANTIC study showed that although pre-hospital administration of ticagrelor did not improve pre-percutaneous coronary intervention (PCI) coronary reperfusion in ACS patients relative to in-hospital administration, ticagrelor was safe in both instances, with no significant between-group differences in non-CABG-related major and minor bleeding events. Although further comparative studies with other antiplatelet agents, including prasugrel, are required to position it more definitively, current evidence indicates that ticagrelor is a useful option for the prevention of thrombotic CV events in ACS patients managed invasively or noninvasively.

Topics: Acute Coronary Syndrome; Adenosine; Administration, Oral; Aging; Combined Modality Therapy; Coronary Artery Bypass; Evidence-Based Medicine; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Risk; Thrombosis; Ticagrelor

Topics: Acute Coronary Syndrome; Adenosine; Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Hemorrhage; Humans; Morpholines; Percutaneous Coronary Intervention; Piperazines; Platelet Aggregation Inhibitors; Postoperative Complications; Prasugrel Hydrochloride; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thrombosis; Ticagrelor

Patients with chronic kidney disease are particularly prone to cardiovascular disorders because of a tendency to thrombosis, but also have an enhanced hemorrhagic risk. The use of antiplatelet agents in this subset of patients is not yet well defined and caution should be given on which AAP is prescribed to them.

Topics: Adenosine; Blood Platelet Disorders; Clopidogrel; Evidence-Based Practice; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Renal Insufficiency, Chronic; Thiophenes; Thrombosis; Ticagrelor; Ticlopidine

In the peripheral arteries, a thrombus superimposed on atherosclerosis contributes to the progression of peripheral artery disease (PAD), producing intermittent claudication (IC), ischemic necrosis, and, potentially, loss of the limb. PAD with IC is often undiagnosed and, in turn, undertreated. The low percentage of diagnosis (∼30%) in this setting of PAD is of particular concern because of the potential worsening of PAD (amputation) and the high risk of adverse vascular outcomes (vascular death, coronary artery disease, stroke). A Medline literature search of the highest-quality systematic reviews and meta-analyses of randomized controlled trials documents that, due to risk of bias, imprecision, and indirectness, the overall quality of the evidence concerning diagnostic tools and antithrombotic interventions in PAD is generally low. Areas of research emerge from the information collected. Appropriate treatments for PAD patients will only derive from ad-hoc studies. Innovative imaging techniques are needed to identify PAD subjects at the highest vascular risk. Whether IC unresponsive to physical exercise and smoking cessation identifies those with a heritable predisposition to more severe vascular events deserves to be addressed. Devising ways to improve prevention of vascular events in patients with PAD implies a co-ordinated approach in vascular medicine.

Topics: Adenosine; Aspirin; Asymptomatic Diseases; Cilostazol; Clopidogrel; Fibrinolytic Agents; Humans; Intermittent Claudication; Ischemia; Lower Extremity; Meta-Analysis as Topic; Myocardial Infarction; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Primary Prevention; Review Literature as Topic; Secondary Prevention; Stroke; Tetrazoles; Thrombosis; Ticagrelor; Ticlopidine

Dual antiplatelet therapy, composed of aspirin plus a P2Y12 -receptor antagonist, is the cornerstone of treatment for patients with acute coronary syndrome (ACS). A number of U.S. Food and Drug Administration-approved P2Y12 -receptor antagonists are available for treating patients with ACS, including the thienopyridine compounds clopidogrel and prasugrel. Ticagrelor, the first of a new class of antiplatelet agents, is a noncompetitive, direct-acting P2Y12 -receptor antagonist. Unlike the thienopyridine compounds, ticagrelor does not require metabolism for activity. Also, whereas clopidogrel and prasugrel are irreversible inhibitors of the P2Y12 receptor, ticagrelor binds reversibly to inhibit receptor signaling and subsequent platelet activation. In pharmacodynamic studies, ticagrelor demonstrated faster onset and more potent inhibition of platelet aggregation than clopidogrel. These properties of ticagrelor may contribute to reduced rates of thrombotic outcomes compared with clopidogrel, as demonstrated in a phase III clinical trial. However, in addition to bleeding, distinctive adverse effects of this new chemical entity have not been reported with the thienopyridine P2Y12 -receptor inhibitors. Although ticagrelor represents an advancement in P2Y12 -receptor inhibition therapy, a thorough understanding of this compound as an antiplatelet therapy remains to be elucidated.

Topics: Acute Coronary Syndrome; Adenosine; Animals; Clinical Trials as Topic; Humans; Purinergic P2Y Receptor Antagonists; Thrombosis; Ticagrelor; Treatment Outcome

Cardiovascular disease and in particular, acute coronary syndromes are one of the principle causes of death in the industrialized countries. In the setting of acute coronary syndromes (both ST - segment or non ST - segment elevation myocardial infarction), platelets aggregation plays a key and central role in their development. Platelets are the mediators of hemostasis at sites of vascular injury, but they also mediate pathologic thrombosis; activated platelets stimulate thrombus formation in response to rupture of an atherosclerotic plaque or endothelial cell erosion promoting atherothrombotic disease. Recent patent relates to the methods and devices for treating atherosclerosis and to prevent in-stent restenosis or thrombosis. Because of the importance of platelets involvement in the initiation and propagation of thrombosis, antiplatelet drugs have a source of research; in the recent past, new antiplatelet drugs (such as ticagrelor) have been studied and placed in the routine therapy. The aim of this paper is to summarize the pharmacological properties and the clinical characteristics of ticagrelor.

Topics: Acute Coronary Syndrome; Adenosine; Animals; Blood Platelets; Cardiovascular Diseases; Humans; Patents as Topic; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Thrombosis; Ticagrelor

The initial 2010 Canadian Cardiovascular Society (CCS) Guidelines for the Use of Antiplatelet Therapy in the Outpatient Setting were published in May 2011. As part of a planned re-evaluation within 2 years, we conducted an extensive literature search encompassing all topics included in the 2010 CCS Guidelines, and concluded that there were sufficient new data to merit revisiting the guidance on antiplatelet therapy for secondary prevention in the first year after acute coronary syndrome (ACS), percutaneous coronary intervention, or coronary artery bypass grafting, and the interaction between clopidogrel and proton pump inhibitors. In addition, new clinical trials information about the efficacy and safety of combining novel oral anticoagulants with antiplatelet therapy in ACS justified the addition of a new section of recommendations to the Guidelines. In this focused update, we provide recommendations for the use of clopidogrel, ticagrelor, and prasugrel in non-ST elevation ACS, avoidance of prasugrel in patients with previous stroke/transient ischemic attack, higher doses of clopidogrel (j) /day) for the first 6 days after ACS, and the preferential use of prasugrel or ticagrelor after percutaneous coronary intervention in ACS. For non-ACS stented patients, we recommend acetylsalicylic acid/clopidogrel for 1 year, with at least 1 month of therapy for bare-metal stent patients and 3 months for drug-eluting stent patients unable to tolerate year-long double therapy. We also consider therapy for patients with a history of stent thrombosis, the indications for longer-term treatment, discontinuation timing preoperatively, indications for changing agents, the management of antiplatelet therapy before and after bypass surgery, and use/selection of proton pump inhibitors along with antiplatelet agents.

Topics: Acute Coronary Syndrome; Adenosine; Anticoagulants; Aspirin; Clinical Trials as Topic; Clopidogrel; Contraindications; Coronary Artery Bypass; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Hemorrhage; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Proton Pump Inhibitors; Secondary Prevention; Stents; Stroke; Thiophenes; Thrombosis; Ticagrelor; Ticlopidine

Topics: Acute Coronary Syndrome; Adenosine; Drug Administration Schedule; Drug Costs; Humans; Myocardial Infarction; Purinergic P2Y Receptor Antagonists; Stroke; Thrombosis; Ticagrelor; United States

The two newer antiplatelet drugs, prasugrel and ticagrelor have both been incorporated in various national guidelines and are both under consideration for approval or have already been approved by various drug regulatory authorities. Mortality benefits with clopidogrel were comparable to newer anti-platelets, and prasugrel had great anti-ischemic potency than ticagrelor. We searched PubMed, EMBASE and Cochrane Central Register of Controlled Trials' databases for randomized controlled trials conducted between 1990 and 2012 that assessed clinical outcomes with prasugrel or ticagrelor. The comparator was standard dosage of clopidogrel. Outcomes assessed were the risk of all causes mortality, TIMI non-CABG major bleeding, and a composite of stent thrombosis, recurrent ischemia and serious recurrent ischemia in the intervention groups versus the comparator groups. Event rates were compared using a forest plot of relative risk using a random effects model (Mantel-Haenszel); and Odd's ratio was calculated in the absence of significant heterogeneity. Prasugrel was indirectly compared with ticagrelor using network meta-analysis. Four studies (total N = 34,126) met the inclusion/exclusion criteria. Both drugs had improved mortality and greater risk of bleeding compared to clopidogrel; but outcomes were comparable for both (p = NS). However a composite of recurrent ischemic events, including rates of stent thrombosis (p = 0.045) was reduced to a modest degree with prasugrel compared with ticagrelor. This systematic review suggests greater clinical efficacy of both prasugrel and ticagrelor compared with clopidogrel and an indirect comparison indicates prasugrel may be more effective than ticagrelor for preventing stent thrombosis and recurrent ischemic events.

Topics: Adenosine; Clopidogrel; Hemorrhage; Humans; Ischemia; Piperazines; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Prasugrel Hydrochloride; PubMed; Randomized Controlled Trials as Topic; Stents; Thiophenes; Thrombosis; Ticagrelor; Ticlopidine

Antiplatelet therapy is used widely with proven benefit for the prevention of further ischemic cardiac complications in patients with known coronary artery disease (CAD) and a history of acute coronary syndrome (ACS). The limitations of conventional antiplatelet therapy with aspirin, clopidogrel, or prasugrel, as well as the fact that rates of recurrent ischemic events still remain high with use of these agents, underscore the need to investigate alternate agents that may further reduce event rates while limiting bleeding risk. The selection of antiplatelet therapy is further influenced by the following: ticagrelor was approved in July 2011 by the United States Food and Drug Administration (FDA), and clopidogrel is slated to become available as a generic productin 2012. We provide an overview of emerging agents for the treatment of CAD and ACS, including the reversible P2Y(12) antagonists ticagrelor, cangrelor, and elinogrel, and a new class of oral protease-activated receptor-1 (PAR-1) inhibitors, vorapaxar and atopaxar.The recently approved P2Y(12) antagonists prasugrel and ticagrelor demonstrate enhanced ability to prevent adverse cardiac outcomes. However, this comes at a cost of a potential increased risk of bleeding. New adverse effects have also emerged, including dyspnea for all of the reversible P2Y(12) antagonists (ticagrelor, cangrelor, and elinogrel) and ventricular pauses for ticagrelor. In addition, the newer P2Y(12) antagonists have a faster onset and offset. Two of these agents, cangrelor and elinogrel, are available as intravenous formulations, which may provide additional benefits in patients who undergo coronary artery bypass graft (CABG) surgery. Trials with the PAR-1 inhibitors have also shown trends toward reductions in cardiac events, but not without the possibility of increased bleeding. More than ever, as the arsenal of antiplatelet therapy expands, health care providers need to understand the pharmacologic and pharmacodynamic differences between conventional and emerging antiplatelet therapies for patients with ACS and CAD. Health care providers must also carefully assess patient-specific factors such as risk of thrombosis, concomitant disease states, age, drug adherence, and aspirin dose, and plan for those patients who will be undergoing CABG when selecting antiplatelet therapy in order to optimally balance bleeding and thrombosis risk.

Topics: Acute Coronary Syndrome; Adenosine; Animals; Clinical Trials as Topic; Coronary Artery Disease; Hemorrhage; Humans; Imines; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Thiophenes; Thrombosis; Ticagrelor

Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker is a well-established strategy to prevent thrombotic complications in patients with acute coronary syndromes (ACS) and after percutaneous coronary interventions (PCI). Current practice guidelines for antiplatelet therapy advocate a 1 to 12-month dual antiplatelet therapy after bare metal stent PCI and an up to 12-month dual antiplatelet therapy after PCI in patients with ACS and drug-eluting stent PCI. Premature withdrawal of dual antiplatelet therapy carries a substantial risk of stent thrombosis but perioperative continuation of dual antiplatelet therapy is associated with an increased risk of bleeding, particularly in patients treated with the new potent drugs prasugrel and ticagrelor. Based on the various available assays, the lack of validated cut-offs and the disappointing results of targeted antiplatelet therapy as demonstrated by the GRAVITAS trial, current guidelines of international societies recommend platelet function testing only for selected high risk patients despite the known association between clopidogrel low responsiveness and ischemic events. However, for individual patients taking clopidogrel, platelet function monitoring may be considered to safely shorten the preoperative waiting period, to assess the risk of bleeding and transfusion and to initiate specific therapy in bleeding patients.

Topics: Adenosine; Angioplasty, Balloon, Coronary; Clopidogrel; Humans; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Point-of-Care Systems; Postoperative Complications; Postoperative Hemorrhage; Practice Guidelines as Topic; Prasugrel Hydrochloride; Predictive Value of Tests; Stents; Thiophenes; Thrombosis; Ticagrelor; Ticlopidine

ADP plays a pivotal role in localized platelet activation and recruitment, and, with that, in the maintenance of thrombus integrity, making it a suitable target for the control of intravascular thrombosis. The limited distribution of one of its receptors, the P2Y12 receptor, primarily to platelets makes it an especially attractive pharmacologic target. For the last several decades the thienopyridine family of P2Y12 antagonists have provided the vast majority of clinical data confirming the clinical benefit of selective P2Y12 inhibition. Recently, new thienopyridine plus nonthienopyridine P2Y12 antagonists have become available or are being studied that will further improve our treatment of patients with coronary disease.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Clopidogrel; Coronary Artery Disease; Humans; Myocardial Infarction; Piperazines; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Quinazolinones; Stents; Sulfonamides; Thiophenes; Thrombosis; Ticagrelor; Ticlopidine

The important role of the P2Y12 receptor in amplification of platelet activation and associated responses and the limitations associated with clopidogrel therapy have led to the development of novel inhibitors of this receptor. Three reversibly-binding P2Y12 inhibitors are in phase 3 development, ticagrelor, cangrelor and elinogrel. The pharmacology and clinical trial data for each of these inhibitors are discussed and compared with relevant data for the thienopyridines clopidogrel and prasugrel.

Topics: Adenosine; Adenosine Monophosphate; Animals; Clinical Trials, Phase III as Topic; Clopidogrel; Humans; Piperazines; Platelet Activation; Prasugrel Hydrochloride; Protein Binding; Purinergic P2Y Receptor Antagonists; Quinazolinones; Sulfonamides; Thiophenes; Thrombosis; Ticagrelor; Ticlopidine

Inhibition of the platelet ADP P2Y(12) receptor has shown to be associated with a marked risk reduction of atherothrombotic events in high-risk settings, including patients with acute coronary syndromes and those undergoing percutaneous coronary interventions. Clinical and laboratory experiences have led to a better comprehension of the drawbacks of currently available P2Y(12) receptor antagonists, stimulating the development of novel agents. Ticagrelor (AZD6140) is the first drug of a new chemical class called cyclopentyltriazolopyrimidine, which is administered orally and has a reversible P2Y(12) receptor inhibitory effect. Preclinical and early-phase clinical studies have shown ticagrelor to be characterized by a rapid, greater and consistent antiplatelet effect with a favorable safety profile. Recent findings from large-scale Phase III trials showed ticagrelor to be more effective in preventing ischemic events in acute coronary syndrome patients without an increased risk of protocol-defined major bleeding, but with an increase in the rate of nonprocedure-related bleeding, compared with currently recommended treatment regimens. This article provides an overview of the pharmacologic properties and clinical development of ticagrelor.

Topics: Acute Coronary Syndrome; Adenosine; Animals; Clinical Trials as Topic; Humans; Platelet Activation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor

Atherothrombosis, thrombus formation as a result of atherosclerotic plaque rupture, is a major modern health problem, often underlying coronary artery disease, stroke, and peripheral arterial disease. After the treatment of an acute thrombotic episode, long-term therapy is warranted as a secondary prophylaxis of such events and their complications. Because of the importance of platelets' involvement in the initiation and propagation of thrombosis, antiplatelet drugs have come to the forefront of atherothrombotic disease treatment. Dual antiplatelet therapy of aspirin plus clopidogrel--the current standard--has its benefits, but it also has its limitations with regard to its pharmacologic properties and adverse effects. For these reasons, within the last decade or so, the investigation of novel antiplatelet agents has prospered. Here, we review the main pathways through which platelets participate in acute thrombosis and the interruption of these pathways by using novel antiplatelet agents, including P2Y12 receptor antagonists (the recently approved prasugrel, the probable next-in-line ticagrelor, and others). The need for a more individualized patient therapy is evident; although most of the aforementioned pharmaceuticals have the potential to contribute to this, their clinical utility remains to be seen.

Topics: Adenosine; Animals; Blood Platelets; Drugs, Investigational; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor; Treatment Outcome

High platelet reactivity has been linked to recurrent ischemic events in patients treated with conventional dual antiplatelet therapy, in patients with arterial diseases and particularly in patients treated with coronary artery stenting. The limitations of clopidogrel have served as a major rationale for the development of new P2Y(12) blockers that have superior pharmacodynamic profiles uninfluenced by concomitant therapies or specific genotypes. Ticagrelor is the first direct-acting reversibly binding oral P2Y(12) receptor antagonist. Extensive Phase II investigations have addressed the pharmacokinetic, pharmacodynamic and safety-related properties of ticagrelor compared with clopidogrel. The recently completed PLATO trial demonstrated promise for ticagrelor as a major treatment strategy for a wide spectrum of patients with acute coronary syndromes. Ticagrelor is now being reviewed by the FDA as a P2Y(12) receptor blocker to treat patients with coronary artery disease and, once accepted, will be in widespread use as an antiplatelet agent. Thus, it is both appropriate and timely to review available data and provide a comprehensive review of ticagrelor.. We discuss the rationale for the development of ticagrelor, a reversible and potent P2Y(12) receptor blocker. The data regarding ticagrelor based on preclinical and clinical studies are examined. We researched articles about 'AZD6140' and 'ticagrelor' in PubMed from 2006 to 2010 and also reviewed data presented at recent cardiology meetings.. This is an updated and comprehensive review of ticagrelor. The advantages and disadvantages of ticagrelor and available P2Y(12) receptor blockers such as clopidogrel and prasugrel are discussed, thus providing a clear picture to readers.. Ticagrelor has an important role as an antiplatelet agent in the settings of acute coronary syndrome and percutaneous coronary intervention and once accepted will be in widespread use.

Topics: Adenosine; Arteries; Clinical Trials as Topic; Coronary Artery Disease; Humans; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor; Treatment Outcome

ADP is one of the most important mediators of both physiologic hemostasis and thrombosis. Development and utilization of agents that block ADP receptors on the platelet membrane, namely thienopyridines, has represented a major advancement for treatment of patients undergoing percutaneous coronary interventions and those with acute coronary syndromes. Currently, clopidogrel, a second-generation thienopyridine that inhibits the ADP P2Y(12) receptor, represents the treatment of choice, in addition to aspirin, for the prevention of stent thrombosis. Further, long-term adjunctive use of this ADP P2Y(12) receptor antagonist is also associated with improved clinical outcomes in high-risk patients, and represents the standard of care for these patients. Despite the unambiguous clinical benefit associated with clopidogrel, accumulating experience with this drug has also led to identification of some of its drawbacks, which are related to inadequate platelet inhibition with standard dosage regimens as well as to its irreversible antiplatelet effects. This has led to the questioning of currently recommended clopidogrel dosage regimens as well as to the development of novel and more potent ADP P2Y(12) receptor antagonists, some of which are also reversible agents. Numerous studies are currently ongoing with the objective of demonstrating how more potent platelet inhibition using higher loading and maintenance dose regimens of clopidogrel or novel ADP P2Y(12) receptor antagonists - such as prasugrel, ticagrelor (AZD 6140) and cangrelor - will affect clinical outcomes. This article reviews the current knowledge of platelet ADP P2Y(12) receptor antagonism and the projected developments in this field.

Topics: Adenosine; Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Blood Platelets; Clopidogrel; Coronary Disease; Humans; Membrane Proteins; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Thiophenes; Thrombosis; Ticagrelor; Ticlopidine

An important role for adenosine diphosphate (ADP)-induced platelet activation and aggregation was proposed more than 40 years ago. The clinical use of clopidogrel, a prodrug of an irreversible P2Y (12) antagonist, has further proved the relevance of inhibiting signaling via the platelet-specific P2Y (12) ADP receptor in the prevention of cardiovascular events. Pharmacological studies at AstraZeneca R&D Charnwood have identified direct, selective, and competitive P2Y (12) antagonists, including cangrelor (also known as AR-C69931MX), which is suitable for intravenous administration, and AZD6140, which is suitable for oral administration. In preclinical use, these compounds predictably and effectively inhibited platelet aggregation without significant increases in bleeding time. In clinical use, these compounds may have significant advantages over current antiplatelet agents. This article summarizes preclinical and clinical data on cangrelor and AZD6140 and discusses the potential of these compounds as novel antiplatelet therapies.

Topics: Adenosine; Adenosine Diphosphate; Adenosine Monophosphate; Administration, Oral; Animals; Arterial Occlusive Diseases; Clinical Trials as Topic; Dogs; Double-Blind Method; Drug Evaluation, Preclinical; Female; Fibrinolytic Agents; Humans; Injections, Intravenous; Male; Membrane Proteins; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Pyridines; Rabbits; Randomized Controlled Trials as Topic; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor

No study has compared pharmacologic properties of ticagrelor and clopidogrel in non-dialysis patients with stage 4-5 chronic kidney disease (CKD).. We conducted a double-blind RCT to compare effects of ticagrelor and clopidogrel in 48 CKD, with the primary outcome of ADP-induced platelet aggregation (WBPA) after 2 weeks of DAPT. In a parallel arm, we compared effects of 2 weeks of ticagrelor plus aspirin on mean changes in WBPA and markers of thromboinflammation among non-CKD controls (n = 26) with that of CKD in the ticagrelor-arm.. Average age of CKD was 53.7 years, with 62% women, 54% African American, and 42% with stage 5 CKD. Ticagrelor generated statistically lower WBPA values post treatment [median 0 Ω (IQR 0, 2)] vs. clopidogrel [median 0 Ω (IQR 0, 5)] (P = 0.002); percent inhibition of WBPA was greater (87 ± 22% vs. 63 ± 50%; P = 0.04; and plasma IL-6 levels were much lower (8.42 ± 1.73 pg/ml vs. 18.48 ± 26.56 pg/ml; P = 0.04). No differences in mean changes in WBPA between CKD-ticagrelor and control groups were observed. Ticagrelor- DAPT reduced levels of IL-1α and IL-1β in CKD-ticagrelor and control groups, attenuated lowering of TNFα and TRAIL levels in CKD-ticagrelor (vs controls), and had global changes in correlation between various cytokines in a subgroup of CKD-ticagrelor subjects not on statins (n = 10). Peak/trough levels of ticagrelor/metabolite were not different between CKD-ticagrelor and control groups.. We report significant differences in platelet aggregation and anti-inflammatory properties between ticagrelor- and clopidogrel-based DAPT in non-dialysis people with stage 4-5 CKD. These notable inflammatory responses suggest ticagrelor-based DAPT might lower inflammatory burden of asymptomatic patients with stage 4 or 5 CKD. (clinicaltrials.gov # NCT03649711).

Topics: Adenosine; Clopidogrel; Female; Humans; Inflammation; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Renal Insufficiency, Chronic; Thrombosis; Ticagrelor; Ticlopidine; Treatment Outcome

Platelets represent a potential therapeutic target for improved clinical outcomes in patients with COVID-19.. To evaluate the benefits and risks of adding a P2Y12 inhibitor to anticoagulant therapy among non-critically ill patients hospitalized for COVID-19.. An open-label, bayesian, adaptive randomized clinical trial including 562 non-critically ill patients hospitalized for COVID-19 was conducted between February 2021 and June 2021 at 60 hospitals in Brazil, Italy, Spain, and the US. The date of final 90-day follow-up was September 15, 2021.. Patients were randomized to a therapeutic dose of heparin plus a P2Y12 inhibitor (n = 293) or a therapeutic dose of heparin only (usual care) (n = 269) in a 1:1 ratio for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor.. The composite primary outcome was organ support-free days evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and, for those who survived to hospital discharge, the number of days free of respiratory or cardiovascular organ support up to day 21 of the index hospitalization (range, -1 to 21 days; higher scores indicate less organ support and better outcomes). The primary safety outcome was major bleeding by 28 days as defined by the International Society on Thrombosis and Hemostasis.. Enrollment of non-critically ill patients was discontinued when the prespecified criterion for futility was met. All 562 patients who were randomized (mean age, 52.7 [SD, 13.5] years; 41.5% women) completed the trial and 87% received a therapeutic dose of heparin by the end of study day 1. In the P2Y12 inhibitor group, ticagrelor was used in 63% of patients and clopidogrel in 37%. The median number of organ support-free days was 21 days (IQR, 20-21 days) among patients in the P2Y12 inhibitor group and was 21 days (IQR, 21-21 days) in the usual care group (adjusted odds ratio, 0.83 [95% credible interval, 0.55-1.25]; posterior probability of futility [defined as an odds ratio <1.2], 96%). Major bleeding occurred in 6 patients (2.0%) in the P2Y12 inhibitor group and in 2 patients (0.7%) in the usual care group (adjusted odds ratio, 3.31 [95% CI, 0.64-17.2]; P = .15).. Among non-critically ill patients hospitalized for COVID-19, the use of a P2Y12 inhibitor in addition to a therapeutic dose of heparin, compared with a therapeutic dose of heparin only, did not result in an increased odds of improvement in organ support-free days within 21 days during hospitalization.. ClinicalTrials.gov Identifier: NCT04505774.

Topics: Aged; Aged, 80 and over; Anticoagulants; Clopidogrel; Comorbidity; COVID-19; COVID-19 Drug Treatment; Extracorporeal Membrane Oxygenation; Female; Hemorrhage; Heparin; Hospital Mortality; Humans; Inpatients; Male; Medical Futility; Middle Aged; Outcome Assessment, Health Care; Oxygen Inhalation Therapy; Platelet Activation; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Respiration, Artificial; Thrombosis; Ticagrelor; Time Factors; Treatment Outcome

Ticagrelor provides more rapid, potent, and consistent anti-platelet efficacy than clopidogrel. This randomized trial aimed to evaluate the anti-inflammation effects of ticagrelor versus clopidogrel on thrombus aspirated from the ST-elevation myocardial infarction (STEMI) patients.. A total of 98 patients with STEMI and intended percutaneous coronary intervention (PCI) were randomly assigned to receive clopidogrel (600-mg loading dose) or ticagrelor (180-mg loading dose), of whom 55 with large thrombus burden underwent thrombus aspiration during PCI. Thrombus specimens were successfully aspirated from 49 patients. Finally, 24 patients in the clopidogrel group and 23 in the ticagrelor group completed the study. Inflammatory cells within thrombi were assessed by hematoxylin-eosin and immunohistochemistry stainings.. In patients with undergoing PCI for STEMI, the loading dose ticagrelor regimen was associated with a reduction in inflammatory cell infiltration within thrombus compared with the loading dose clopidogrel regimen.

Topics: Clopidogrel; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; ST Elevation Myocardial Infarction; Thrombosis; Ticagrelor; Treatment Outcome

It remains unclear whether aggressive low-density lipoprotein cholesterol (LDL-C) management (<1.8 mmol/L) can slow the process of vein graft stenosis. This study aimed to explore the impact of baseline LDL-C levels on vein graft patency in patients on ticagrelor with or without aspirin 1 year after coronary artery bypass grafting (CABG).. This was a post hoc analysis of the DACAB (Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery) trial (NCT02201771), a randomized controlled trial (ticagrelor + aspirin or ticagrelor vs aspirin) of patients undergoing CABG in China. The study subjects were stratified as LDL-low (baseline LDL-C <1.8 mmol/L, 148 patients with 430 vein grafts) versus LDL-high (baseline LDL-C ≥1.8 mmol/L, 352 patients with 1030 vein grafts). The primary outcome was the 1-year vein graft patency (Fitzgibbon grade A) assessed by coronary computed tomographic angiography or coronary angiography.. In general, baseline LDL-C is not associated with 1-year vein graft patency after CABG. Regardless of the baseline LDL-C levels, ticagrelor + aspirin was superior to aspirin alone in maintaining vein graft patency. The primary factor causing early vein graft disease might not be atherosclerosis but thrombosis.

Topics: Aged; Aspirin; Biomarkers; China; Cholesterol, LDL; Coronary Artery Bypass; Coronary Artery Disease; Dual Anti-Platelet Therapy; Female; Graft Occlusion, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Platelet Aggregation Inhibitors; Risk Assessment; Risk Factors; Thrombosis; Ticagrelor; Time Factors; Treatment Outcome; Vascular Patency

Topics: Clopidogrel; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Thrombosis; Ticagrelor; Tomography, Optical Coherence

Background Coronary stent type and risk of stent thrombosis remain important factors affecting recommended duration of dual antiplatelet therapy. We investigated the efficacy and safety of long-term ticagrelor in patients with prior coronary stenting enrolled in the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) trial. Methods and Results Patients in PEGASUS-TIMI 54 had a myocardial infarction 1 to 3 year prior and were randomized 1:1:1 to ticagrelor 60 or 90 mg BID or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular events). Stent thrombosis was prospectively adjudicated (Academic Research Consortium definition). Baseline characteristics were compared by most recent stent type (bare metal versus drug-eluting stent and first- versus later-generation drug-eluting stent). Treatment arms were compared using Cox proportional hazards models. Of 21 162 patients randomized, 80% (n=16 891) had prior coronary stenting. Following randomization, myocardial infarction was the most frequent ischemic event in patients with prior stenting in the placebo arm, occurring in 5.2% of patients (Type 1: 4.1%), followed by cardiovascular death (2.3%), stroke (1.7%), and stent thrombosis (0.9%). Ticagrelor

Topics: Drug Therapy, Combination; Drug-Eluting Stents; Hemorrhage; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Secondary Prevention; Stents; Stroke; Thrombosis; Ticagrelor; Treatment Outcome

Women experience worse ischemic and bleeding outcomes after percutaneous coronary intervention (PCI).. To assess the association of sex with patient outcomes at 2 years after contemporary PCI and with the efficacy and safety of 2 antiplatelet strategies.. This study is a prespecified subgroup analysis of the investigator-initiated, prospective, randomized GLOBAL LEADERS study evaluating 2 strategies of antiplatelet therapy after PCI in an unselected population including 130 secondary/tertiary care hospitals in different countries. The main study enrolled 15 991 unselected patients undergoing PCI between July 2013 and November 2015. Patients had an outpatient clinic visit at 30 days and 3, 6, 12, 18, and 24 months after the index procedure. Data were analyzed between January 1, 2019, and March 31, 2019.. Eligible patients were randomized to either the experimental or reference antiplatelet strategy. Experimental strategy consisted of 1 month of dual antiplatelet therapy (DAPT) followed by 23 months of ticagrelor monotherapy, while the reference strategy comprised of 12 months of DAPT followed by 12 months of aspirin monotherapy.. The primary efficacy end point was the composite of all-cause mortality and new Q-wave myocardial infarction at 2 years. The secondary safety end point was Bleeding Academic Research Consortium type 3 or 5 bleeding.. Of the 15 968 patients included in this study, 3714 (23.3%) were women. The risk of the primary end point at 2 years was similar between women and men (adjusted hazard ratio [HR], 1.00; 95% CI, 0.83-1.20). Compared with men, women had higher risk of Bleeding Academic Research Consortium type 3 or 5 bleeding (adjusted HR, 1.32; 95% CI, 1.04-1.67) and hemorrhagic stroke at 2 years (adjusted HR, 4.76; 95% CI, 1.92-11.81). At 2 years, there was no between-sex difference in the efficacy and safety of the 2 antiplatelet strategies. At 1 year, compared with DAPT, ticagrelor monotherapy was associated with a lower risk of bleeding in men (HR, 0.72; 95% CI, 0.53-0.98) but not in women (HR, 1.23; 95% CI, 0.80-1.89; P for interaction = .045).. Compared with men, women experienced a higher risk of bleeding and hemorrhagic stroke after PCI. The effect of 2 antiplatelet strategies on death and Q-wave myocardial infarction following PCI did not differ between the sexes at 2 years.. ClinicalTrials.gov identifier: NCT01813435.

Topics: Aged; Aspirin; Coronary Artery Disease; Drug-Eluting Stents; Dual Anti-Platelet Therapy; Female; Hemorrhage; Hemorrhagic Stroke; Humans; Ischemic Stroke; Male; Middle Aged; Mortality; Myocardial Infarction; Myocardial Revascularization; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Proportional Hazards Models; Secondary Prevention; Sex Factors; Thrombosis; Ticagrelor

 Glycoprotein IIb/IIIa inhibitors (GPIs) in combination with clopidogrel improve clinical outcome in ST-elevation myocardial infarction (STEMI); however, finding a balance that minimizes both thrombotic and bleeding risk remains fundamental. The efficacy and safety of GPI in addition to ticagrelor, a more potent P2Y12-inhibitor, have not been fully investigated..  1,630 STEMI patients who underwent primary percutaneous coronary intervention (PCI) were analyzed in this subanalysis of the ATLANTIC trial. Patients were divided in three groups: no GPI, GPI administration routinely before primary PCI, and GPI administration in bailout situations. The primary efficacy outcome was a composite of death, myocardial infarction, urgent target revascularization, and definite stent thrombosis at 30 days. The safety outcome was non-coronary artery bypass graft (CABG)-related PLATO major bleeding at 30 days..  Use of GPIs in addition to ticagrelor in STEMI patients was not associated with an improvement in 30-day ischemic outcome. A significant increase in 30-day non-CABG-related PLATO major bleeding was seen in patients who received GPIs in a bailout situation.

Topics: Aged; Clopidogrel; Double-Blind Method; Drug Therapy, Combination; Female; Hemorrhage; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Postoperative Complications; ST Elevation Myocardial Infarction; Survival Analysis; Thrombosis; Ticagrelor; Treatment Outcome

Impaired endogenous fibrinolysis is novel biomarker that can identify patients with ACS at increased cardiovascular risk. The addition of Very Low Dose Rivaroxaban (VLDR) to dual antiplatelet therapy has been shown to reduce cardiovascular events but at a cost of increased bleeding and is therefore not suitable for all-comers. Targeted additional pharmacotherapy with VLDR to improve endogenous fibrinolysis may improve outcomes in high-risk patients, whilst avoiding unnecessary bleeding in low-risk individuals. The VaLiDate-R study (ClinicalTrials.gov Identifier: NCT03775746, EudraCT: 2018-003299-11) is an investigator-initiated, randomised, open-label, single centre trial comparing the effect of 3 antithrombotic regimens on endogenous fibrinolysis in 150 patients with ACS. Subjects whose screening blood test shows impaired fibrinolytic status (lysis time > 2000s), will be randomised to one of 3 treatment arms in a 1:1:1 ratio: clopidogrel 75 mg daily (Group 1); clopidogrel 75 mg daily plus rivaroxaban 2.5 mg twice daily (Group 2); ticagrelor 90 mg twice daily (Group 3), in addition to aspirin 75 mg daily. Rivaroxaban will be given for 30 days. Fibrinolytic status will be assessed during admission and at 2, 4 and 8 weeks. The primary outcome measure is the change in fibrinolysis time from admission to 4 weeks follow-up, using the Global Thrombosis Test. If VLDR can improve endogenous fibrinolysis in ACS, future large-scale studies would be required to assess whether targeted use of VLDR in patients with ACS and impaired fibrinolysis can translate into improved clinical outcomes, with reduction in major adverse cardiovascular events in this high-risk cohort.

Topics: Acute Coronary Syndrome; Clopidogrel; Dose-Response Relationship, Drug; Dual Anti-Platelet Therapy; Factor Xa Inhibitors; Female; Fibrinolysis; Humans; Male; Platelet Aggregation Inhibitors; Rivaroxaban; Thrombelastography; Thrombosis; Ticagrelor

An evolving strategy in the setting of percutaneous coronary intervention (PCI) involves withdrawal of acetylsalicylic acid (ASA), or aspirin, while maintaining P2Y. This study sought to compare the antithrombotic potency of ticagrelor alone versus ticagrelor plus ASA among high-risk patients undergoing PCI with drug-eluting stents.. This was a mechanistic substudy within the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial, which randomized patients undergoing PCI to ticagrelor plus placebo versus ticagrelor plus ASA following 3 months of dual antiplatelet therapy. Substudy participants were enrolled after randomization, at which time ex vivo assays to quantify thrombus size under dynamic flow conditions and platelet reactivity were performed. Pharmacodynamic assessments were repeated 1 to 6 months thereafter. The primary endpoint was thrombus size at the post-randomization visit with platelet reactivity following stimuli to arachidonic acid, collagen, adenosine diphosphate, and thrombin as secondary endpoints. Results were analyzed using analysis of covariance.. A total of 51 patients were enrolled, among whom 42 underwent perfusion assays at baseline and follow-up with a median time between studies of 1.5 months. The adjusted mean difference in post-randomization thrombus area was similar between groups: -218.2 μm. Among high-risk patients receiving drug-eluting stents, the antithrombotic potency of ticagrelor monotherapy is similar to that of ticagrelor plus ASA with respect to ex vivo blood thrombogenicity, whereas markers sensitive to cyclo-oxygenase-1 blockade are increased in the absence of ASA. (Platelet Substudy of the TWILIGHT Trial; NCT04001374).

Topics: Aged; Aspirin; Blood; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Complications; Thrombosis; Ticagrelor

Chronic kidney disease (CKD) is associated with an increased risk of acute coronary syndrome (ACS) and cardiovascular death. CKD patients suffering from ACS are exposed to an increased risk of thrombotic recurrences and a higher bleeding rate than patients with normal renal function. However, CKD patients are excluded or underrepresented in clinical trials. Therefore, determining the optimal antiplatelet strategy in this population is of utmost importance. We designed the TicagRelor Or Clopidogrel in severe or terminal chronic kidney patients Undergoing PERcutaneous coronary intervention for acute coronary syndrome (TROUPER) trial: a prospective, controlled, multicenter, randomized trial to investigate the optimal P2Y12 antagonist in CKD patients with ACS. Patients with stage ≥3b CKD are eligible if the diagnosis of ACS is made and invasive strategy scheduled. Patients are randomized 1:1 between a control group with a 600-mg loading dose of clopidogrel followed by a 75-mg/d maintenance dose for 1 year and an experimental group with a 180-mg loading dose of ticagrelor followed by a 90-mg twice daily maintenance dose for the same duration. The primary end point is defined by the rate of major adverse cardiovascular events, including death, myocardial infarction, urgent revascularization, and stroke at 1 year. Safety will be evaluated by the bleeding rate (Bleeding Academic Research Consortium). To demonstrate the superiority of ticagrelor on major adverse cardiovascular events, we calculated that 508 patients are required. The aim of the TROUPER trial is to compare the efficacy of ticagrelor and clopidogrel in stage >3b CKD patients presenting with ACS and scheduled for an invasive strategy. RCT# NCT03357874.

Topics: Acute Coronary Syndrome; Adolescent; Adult; Aged; Clopidogrel; Female; Hemorrhage; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Renal Insufficiency, Chronic; Secondary Prevention; Thrombosis; Ticagrelor; Young Adult

To evaluate if ticagrelor, an effective platelet inhibitor without known non-responders, could inhibit growth of small abdominal aortic aneurysms (AAAs).. In this multi-centre randomized controlled trial, double-blinded for ticagrelor and placebo, acetylic salicylic acid naïve patients with AAA and with a maximum aortic diameter 35-49 mm were included. The primary outcome was mean reduction in log-transformed AAA volume growth rate (%) measured with magnetic resonance imaging (MRI) at 12 months compared with baseline. Secondary outcomes include AAA-diameter growth rate and intraluminal thrombus (ILT) volume enlargement rate. A total of 144 patients from eight Swedish centres were randomized (72 in each group). MRI AAA volume increase was 9.1% for the ticagrelor group and 7.5% for the placebo group (P = 0.205) based on intention-to-treat analysis, and 8.5% vs. 7.4% in a per-protocol analysis (P = 0.372). MRI diameter change was 2.5 mm vs. 1.8 mm (P = 0.113), US diameter change 2.3 mm vs. 2.2 mm (P = 0.778), and ILT volume change 12.9% vs. 10.4% (P = 0.590).. In this RCT, platelet inhibition with ticagrelor did not reduce growth of small AAAs. Whether the ILT has an important pathophysiological role for AAA growth cannot be determined based on this study due to the observed lack of thrombus modulating effect of ticagrelor.. The TicAAA trial is registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT02070653.

Topics: Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal; Disease Progression; Double-Blind Method; Female; Hemorrhage; Humans; Magnetic Resonance Angiography; Male; Middle Aged; Platelet Aggregation Inhibitors; Sweden; Thrombosis; Ticagrelor; Time Factors; Treatment Outcome

Data on optimal antiplatelet treatment regimens in patients who undergo multivessel percutaneous coronary intervention (PCI) are sparse.. This post hoc study investigated the impact of an experimental strategy (1-month dual antiplatelet therapy [DAPT] followed by 23-month ticagrelor monotherapy) versus a reference regimen (12-month DAPT followed by 12-month aspirin monotherapy) according to multivessel PCI.. The GLOBAL LEADERS trial is a prospective, multicenter, open-label, randomized controlled trial, allocating all-comer patients in a 1:1 ratio to either the experimental strategy or the reference regimen. The primary endpoint was the composite of all-cause death or new Q-wave myocardial infarction at 2 years. The secondary safety endpoint was Bleeding Academic Research Consortium type 3 or 5 bleeding.. Long-term ticagrelor monotherapy following 1-month DAPT can favorably balance ischemic and bleeding risks in patients with multivessel PCI. These findings should be interpreted as hypothesis-generating and need to be replicated in future dedicated randomized trials. (GLOBAL LEADERS: A Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation; NCT01813435).

Topics: Aged; Aspirin; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Patient Safety; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Proportional Hazards Models; Prospective Studies; Risk; Stroke; Thrombosis; Ticagrelor; Treatment Outcome

The optimal anti-coagulation strategy for patients with non-ST-elevation myocardial infarction treated with percutaneous coronary intervention is unclear in contemporary clinical practice of radial access and potent P2Y12-inhibitors. The aim of this study was to investigate whether bivalirudin was superior to heparin monotherapy in patients with non-ST-elevation myocardial infarction without routine glycoprotein IIb/IIIa inhibitor use.. In a large pre-specified subgroup of the multicentre, prospective, randomised, registry-based, open-label clinical VALIDATE-SWEDEHEART trial we randomised patients with non-ST-elevation myocardial infarction undergoing percutaneous coronary intervention, treated with ticagrelor or prasugrel, to bivalirudin or heparin monotherapy with no planned use of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention. The primary endpoint was the rate of a composite of all-cause death, myocardial infarction or major bleeding within 180 days.. Bivalirudin as compared to heparin during percutaneous coronary intervention for non-ST-elevation myocardial infarction did not reduce the composite of all-cause death, myocardial infarction or major bleeding in non-ST-elevation myocardial infarction patients receiving current recommended treatments with modern P2Y12-inhibitors and predominantly radial access.

Topics: Aged; Anticoagulants; Antithrombins; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Myocardial Infarction; Non-ST Elevated Myocardial Infarction; Peptide Fragments; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Recombinant Proteins; Stents; Sweden; Thrombosis; Ticagrelor

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.

Topics: Acute Coronary Syndrome; Aged; Female; Humans; Male; Middle Aged; Models, Cardiovascular; Morphine; Percutaneous Coronary Intervention; Platelet Activation; Platelet Aggregation Inhibitors; Prospective Studies; Regression Analysis; Risk Factors; ST Elevation Myocardial Infarction; Thrombosis; Ticagrelor

Patients with type 2 diabetes mellitus (T2DM) are at higher risk of thrombotic complications. Studies have indicated that patients with T2DM have impaired clopidogrel-induced antiplatelet effect. Ticagrelor and prasugrel are two latest generation P2Y. This study, involving 140 patients with T2DM following percutaneous coronary intervention (PCI), evaluated the efficacy of aspirin upon concomitant use of prasugrel (10 mg/d) or ticagrelor (90 mg/d). Platelet reactivity was assessed by value of ADP-induced light transmittance aggregometry (LTA) and vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index (VASP-PRI) at baseline, 7 and 30 days after randomized P2Y. Although ticagrelor and prasugrel have similar platelet inhibitory effects in patients with T2DM, if a P2Y

Topics: Adenosine; Aged; Aspirin; Coronary Disease; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prospective Studies; Purinergic P2Y Receptor Antagonists; Thrombosis; Ticagrelor; Time Factors

Patients with prior myocardial infarction (MI) and multivessel coronary disease (MVD) are at high risk for recurrent coronary events.. The authors investigated the efficacy and safety of ticagrelor versus placebo in patients with MVD in the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54) trial.. Patients with a history of MI 1 to 3 years before inclusion in the PEGASUS-TIMI 54 trial were stratified in a pre-specified analysis based on the presence of MVD. The effect of ticagrelor (60 mg and 90 mg) on the composite of cardiovascular death, MI, or stroke (major adverse cardiovascular events [MACE]), as well as the composite of coronary death, MI, or stent thrombosis (coronary events), and on TIMI major bleeding, intracranial hemorrhage (ICH), and fatal bleeding were evaluated over a median of 33 months.. A total of 12,558 patients (59.4%) had MVD. In the placebo arm, compared with patients without MVD, those with MVD were at higher risk for MACE (9.37% vs. 8.57%, adjusted hazard ratio [HR. Patients with prior MI and MVD are at increased risk of MACE and coronary events, and experience substantial relative and absolute risk reductions in both outcomes with long-term ticagrelor treatment relative to those without MVD. Ticagrelor increases the risk of TIMI major bleeding, but not ICH or fatal bleeding. For patients with prior MI and MVD, ticagrelor is an effective option for long-term antiplatelet therapy. (Prevention of Cardiovascular Events [e.g., Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS]; NCT01225562).

Topics: Aged; Coronary Artery Disease; Drug Administration Schedule; Female; Humans; Intracranial Hemorrhages; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Secondary Prevention; Stroke; Thrombosis; Ticagrelor

Topics: Aged; Blood Platelets; Clopidogrel; Female; Humans; Ischemia; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Stents; Thrombosis; Ticagrelor; Time Factors; Treatment Outcome

Saphenous vein graft disease remains a major limitation of coronary artery bypass graft surgery (CABG). Up to 20% of vein grafts will occlude within the first year after CABG despite standard aspirin antiplatelet therapy. However, more potent postoperative platelet inhibition with ticagrelor may improve graft patency. The goal of this study will be to evaluate the efficacy of ticagrelor, as compared to aspirin, for the prevention of saphenous vein graft occlusion following CABG.. The Ticagrelor Antiplatelet Therapy to Reduce Graft Events and Thrombosis (TARGET) study is a multi-center double-blind randomized controlled trial enrolling patients who have undergone multi-vessel CABG with at least one saphenous vein graft. Patients are being randomized to receive either aspirin 81 mg twice per day or ticagrelor 90 mg twice per day for 2 years starting within 7 days after surgery. The projected enrollment is 150 patients in each arm (300 total patients). Patients will undergo computed tomography (CT) coronary angiography at 1 and 2 years after surgery to assess the incidence of vein graft occlusion and stenosis.. To our knowledge, this trial is the first prospective study to evaluate the impact of early postoperative ticagrelor on 1- and 2-year graft patency after CABG. Furthermore, it is also the first trial to use a novel antiplatelet agent as a standalone, without aspirin, after CABG. Should ticagrelor reduce the incidence of postoperative graft occlusion, the results of this study will redefine modern antiplatelet management following coronary bypass surgery (ClinicalTrials.govNCT02053909).

Topics: Aftercare; Aged; Aspirin; Coronary Angiography; Coronary Artery Bypass; Coronary Artery Disease; Coronary Vessels; Double-Blind Method; Female; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Saphenous Vein; Thrombosis; Ticagrelor; Vascular Patency

 Ticagrelor is an anti-platelet agent that is indicated for prevention of thrombosis after acute coronary syndrome or intra-coronary artery stent implantation, but it increases the risk of bleeding. Platelet transfusion has the potential to treat or prevent bleeding in patients taking ticagrelor, but the optimal quantity of platelets and timing of administration have not been fully defined..  Ten healthy subjects took ticagrelor in combination with acetylsalicylic acid for 5 days, and had blood collected prior to treatment and at 2, 10, 24, 48, 72 and 96 hours after the last doses. The potential of platelet transfusion to prevent or reverse bleeding was evaluated by mixing subject and donor platelet-rich plasma in vitro in nine different proportions, and measuring adenosine diphosphate-mediated aggregation by light transmission aggregometry. Spontaneous offset of the anti-aggregant effect of ticagrelor occurred gradually and was complete at 72 hours after the last dose. The addition of donor platelets enhanced the recovery. The addition of the equivalent of six apheresis platelet units produced a 50% relative reversal at 10 hours, and > 90% reversal at 24 hours..  Donor platelets enhance reversal of the anti-aggregant effect of ticagrelor in vitro. Donor platelets given in clinically relevant amounts partially reversed ticagrelor at 10 hours after the last dose, and almost fully reversed ticagrelor at 24 hours. The results inform on the potential to reverse ticagrelor in patients who develop bleeding or require emergency surgery.

Topics: Acute Coronary Syndrome; Adenosine Diphosphate; Adult; Blood Platelets; Cells, Cultured; Female; Healthy Volunteers; Hemorrhage; Humans; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Transfusion; Platelet-Rich Plasma; Risk; Thrombosis; Ticagrelor; Young Adult

Objective The CYP2C19 loss-of-function (LoF) allele is present in half of the East Asian population and is associated with high on-treatment platelet reactivity (HTPR). This study aimed to investigate whether a rapid genotyping-guided approach is feasible and efficacious for selecting P2Y12 receptor blockers in Chinese patients suffering from acute coronary syndrome (ACS). Methods This was a single-centre, prospective, randomized, open-label study. A total of 132 patients with ACS were randomized to the rapid genotyping-guided treatment group (GG, N = 65) or the standard treatment group (SG, N = 67). Patients in the GG group were genotyped by the Verigene system. Patients with the CYP2C19 LoF allele were switched to ticagrelor and all remaining patients continued on clopidogrel. The endpoints were HTPR at 24 hours after the first loading dose of clopidogrel and 1 month afterwards. Results Forty patients in the GG group switched to ticagrelor, while others continued on clopidogrel. The incidence of HTPR in the GG vs SG groups was 9.2% vs 40.3% at 24 hours and 6.5% vs 32.3% at 1 month, respectively. Rapid point-of-care genotyping showed 100% concordance with conventional genotyping by real-time polymerase chain reaction. Conclusions In Chinese patients suffering from ACS, the rapid genotyping-guided approach for selecting P2Y12 receptor blockers is feasible and reduces the incidence of HTPR. Clinical Trial Registration URL: http://clinicaltrials.gov . Unique identifier: NCT01994941.

Topics: Acute Coronary Syndrome; Adenosine; Aged; Alleles; Asian People; Blood Platelets; Clopidogrel; Cytochrome P-450 CYP2C19; Female; Gene Expression; Gene Frequency; Genotype; Genotyping Techniques; Humans; Male; Middle Aged; Mutation; Platelet Aggregation; Platelet Aggregation Inhibitors; Prospective Studies; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor; Ticlopidine

Ticagrelor reduced cardiovascular events compared with clopidogrel in PLATO without increasing overall major bleeding. We evaluated whether the use of glycoprotein IIb/IIIa inhibitor (GPI) impacts the relative efficacy and safety of ticagrelor compared with clopidogrel.. PLATO randomized 18,624 subjects with acute coronary syndrome to ticagrelor versus clopidogrel. The primary efficacy end point was cardiovascular death/myocardial infarction/stroke, and the primary safety end point was major bleeding. The use of GPI was at the physician's discretion and open-label. We evaluated outcomes at 30 days stratified by GPI use in the subgroup of 9,983 patients who underwent percutaneous coronary intervention (PCI) within 72 hours.. A total of 4,020 (40%) received a GPI. Those receiving a GPI were more likely to be younger, be male, and undergo multivessel PCI. There was no interaction between treatment and GPI use for the primary efficacy and safety end points. Patients treated without GPI had a lower rate of definite stent thrombosis and higher rate of minor/major bleeding with ticagrelor compared with clopidogrel (P < .05), whereas there was no such difference with GPI (P interaction < .05).. In patients with acute coronary syndrome undergoing early PCI, the efficacy and safety of ticagrelor as compared with clopidogrel were not modified by GPI use according to the primary efficacy and safety end point of the trial, although there were indications of greater benefit on definite stent thrombosis and more major or minor bleeding with ticagrelor in patients without (vs with) GPI treatment.

Topics: Abciximab; Acute Coronary Syndrome; Adenosine; Aged; Antibodies, Monoclonal; Aspirin; Cardiovascular Diseases; Clopidogrel; Drug Therapy, Combination; Drug-Eluting Stents; Eptifibatide; Female; Graft Occlusion, Vascular; Hemorrhage; Humans; Immunoglobulin Fab Fragments; Male; Middle Aged; Myocardial Infarction; Peptides; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Purinergic P2Y Receptor Antagonists; Stroke; Thrombosis; Ticagrelor; Ticlopidine; Tirofiban; Tyrosine

We sought to assess the impact of different oral P2Y12 receptor inhibitors on residual thrombus and reperfusion indexes in ST-segment elevation myocardial infarction patients enrolled in the COCTAIL II trial, which included 128 primary percutaneous coronary interventions randomized to intracoronary vs. intralesion abciximab bolus with or without thrombectomy.. Patients were divided into three groups: clopidogrel (n = 44), prasugrel (n = 45) and ticagrelor (n = 39). Residual intra-stent thrombus was quantified by optical coherence tomography using both the number of cross-sections with thrombus area more than 10% and thrombus volume. Reperfusion indexes included thrombolysis in myocardial infarction (TIMI) flow, corrected TIMI frame count, myocardial blush grade (MBG) and complete ST-segment resolution (≥70%).. In the prasugrel group, optical coherence tomography depicted a lower percentage of cross-sections with residual thrombus area more than 10% [4.0 (1.0-8.5)], as compared with clopidogrel [8.0 (1.0-15.0), P = 0.011] and ticagrelor [7.0 (3.0-13.5), P = 0.026].A higher thrombus volume was found in the clopidogrel group 4.0 mm(2.7-6.2) as compared with the prasugrel group [2.8 mm(1.8-4.4), P = 0.023], whereas the other between-group comparisons yield no significant differences. The frequency of MBG 3 was higher in the prasugrel group (73.3%) as compared with clopidogrel (45.5%) and ticagrelor [(56.4%), P = 0.027]. Final TIMI flow, TIMI frame count and ST resolution were not significantly different across the three groups (P = 0.423, 0.179 and 0.848, respectively). At multivariate analysis, pretreatment with prasugrel was independently associated with MBG 3 (odds ratio = 3.93; 95% confidence interval = 1.01-15.39).. Prasugrel loading dose was associated with a lower percentage of cross-sections with residual thrombus area more than 10% as compared with both clopidogrel and ticagrelor, although intrastent thrombus volume was not significantly different between prasugrel and ticagrelor.The frequency of MBG 3 was the only reperfusion index that was significantly more prevalent in prasugrel treated group as compared with clopidogrel and ticagrelor groups.

Topics: Abciximab; Adenosine; Administration, Oral; Aged; Aged, 80 and over; Antibodies, Monoclonal; Clopidogrel; Coronary Angiography; Electrocardiography; Female; Humans; Immunoglobulin Fab Fragments; Male; Middle Aged; Myocardial Reperfusion; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; ST Elevation Myocardial Infarction; Stents; Thrombectomy; Thrombosis; Ticagrelor; Ticlopidine; Tomography, Optical Coherence

The optimal duration of dual antiplatelet therapy (DAPT) in acute coronary syndrome (ACS) patients treated with drug eluting stents (DES) is still under debate. Recent meta-analyses on ≤6months versus 12months DAPT suggest that bleeding rates can be reduced, without a higher rate of thrombotic complications. In particular, the COMBO dual therapy stent, being associated with early re-endothelialization, may allow for a reduction of the duration of DAPT without increasing the thrombotic risk, while reducing the risk of bleeding complications.. The aim of the REDUCE trial is to demonstrate the non-inferiority of a combined efficacy and safety endpoint of a short-term 3months DAPT strategy as compared to standard 12-month DAPT strategy in ACS patients treated with the COMBO stent.. A prospective, multicenter, randomized study designed to enroll 1500 patients with ACS treated with the COMBO stent. Patients will be randomized before discharge in a 1:1 fashion to either 3 or 12months of DAPT. A clinical follow-up is scheduled at 3, 6, 12, and 24months. The primary endpoint is the time to event as defined by the occurrence of one of the following: all cause mortality, myocardial infarction, stent thrombosis, stroke, target vessel revascularization or bleeding (Bleeding Academic Research Council type II, III and V) within 12months. The study has recruited patients since July 2014, and the results are expected in 2017.. A reduction of the DAPT duration in ACS patients after PCI without affecting the thrombotic risk is an attractive option with regard to the associated bleeding risk. The REDUCE trial will be the first to investigate the efficacy and safety of a 3-month DAPT strategy compared to a 12-month DAPT strategy in an ACS only population treated with the COMBO stent.

Topics: Acute Coronary Syndrome; Adenosine; Aspirin; Cause of Death; Clopidogrel; Coronary Artery Disease; Drug Therapy, Combination; Drug-Eluting Stents; Graft Occlusion, Vascular; Hemorrhage; Humans; Mortality; Myocardial Infarction; Myocardial Revascularization; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Stroke; Thrombosis; Ticagrelor; Ticlopidine; Time Factors

Patients with kidney failure treated with maintenance hemodialysis (HD) are poor responders to clopidogrel. More beneficial platelet-inhibiting strategies in HD patients therefore are required.. Single-center, prospective, randomized, crossover study.. 25 HD patients in Seoul, Korea.. Patients were randomly assigned to receive clopidogrel (300mg loading, 75mg once daily for maintenance dose) or ticagrelor (180mg loading, 90mg twice daily for maintenance dose) for 14 days, and after a 14-day washout period, crossover treatment for another 14 days. All patients received aspirin (100mg/d).. Platelet function was evaluated predosing and at 1, 5, and 48 hours and 14 days after the first loading dose. During the offset phase, platelet function was assessed at 1 hour and 2, 4, and 14 days after the last dose by light transmittance aggregometry and the VerifyNow P2Y12 assay, and patients were genotyped for the CYP2C19*2 allele. Maximal extent of aggregation, inhibition of platelet aggregation (IPA), P2Y12 reaction units (PRUs), and percentage of inhibition were evaluated. We performed per-protocol analysis, excluding patients who did not complete the protocol.. 9 patients did not complete the protocol (7 patients due to adverse events; 2, nonadherence). Higher IPA occurred with ticagrelor than with clopidogrel at 1, 5, and 48 hours and 14 days after loading. By 5 hours after loading, a greater proportion of patients in the ticagrelor group than in the clopidogrel group achieved IPA>50% (75% vs 12%, respectively; P<0.05) and IPA>70% (44% vs 0%, respectively; P<0.05). Rates (slope) of onset and offset of the antiplatelet effect were faster in patients receiving ticagrelor than for those receiving clopidogrel (P<0.05). Regardless of CYP2C19*2 allele, the ticagrelor group had significantly lower PRUs at all times than the clopidogrel group.. Single-center study with a small number of patients, not a double-blind study, and not intention-to-treat analysis.. Ticagrelor may result in more rapid and greater platelet inhibition than clopidogrel in patients with kidney failure receiving HD.

Topics: Adenosine; Adult; Aspirin; Clopidogrel; Cross-Over Studies; Drug Therapy, Combination; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Function Tests; Renal Dialysis; Single-Blind Method; Thrombosis; Ticagrelor; Ticlopidine; Treatment Outcome

There is insufficient data on the efficacy of prasugrel and ticagrelor in Korean patients with ST-segment elevation myocardial infarction (STEMI).. I n the current double-blind, prospective pilot study, 39 patients with STEMI undergoing primary percutaneous coronary intervention were randomized to receive prasugrel 60 mg loading dose (LD) followed by 10 mg daily maintenance dose (n=19), or ticagrelor 180 mg LD followed by 90 mg twice daily maintenance dose (n=20). We assessed platelet reactivity with the VerifyNow and Vasodilator-Stimulated Phosphoprotein (VASP) P2Y12 assays. Compared to baseline platelet reactivity, both prasugrel and ticagrelor groups achieved similar and significantly lower P2Y12 reaction units (PRU) (259 [IQR: 230 to 281] vs. 28 [12 to 55] for prasugrel; 261 [196 to 286] vs. 43 [11 to 61] for ticagrelor), and platelet reactivity indexes (PRI) (51.2% [39.3 to 61.3] vs. 8.1% [6.1 to 14.7] for prasugrel; 47.5% [38.4 to 50.4] vs. 11.2% [7.1 to 15.5] for ticagrelor, all P values <0.001) at 48 h post-LD. Most patients had low platelet reactivity with 95% PRU values <85 and 82% with PRI <16%.. Both prasugrel and ticagrelor were effective for platelet inhibition in Korean STEMI patients with almost no patients exhibiting high platelet reactivity at 48 h after the LD. Our finding of a high number of patients with very low platelet reactivity deserves further studies to assess the safety of the drugs (Prasugrel and Ticagrelor in ST-segment Elevation Myocardial Infarction Study, NCT02075125).

Topics: Adenosine; Adult; Aged; Asian People; Aspirin; Cardiac Catheterization; Double-Blind Method; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Pilot Projects; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Postoperative Complications; Prasugrel Hydrochloride; Prospective Studies; Purinergic P2Y Receptor Antagonists; Republic of Korea; Sample Size; Thrombophilia; Thrombosis; Ticagrelor

Clinical studies suggest that platelet P2Y12 inhibitors reduce mortality from sepsis, although the underlying mechanisms have not been clearly defined in vivo. We hypothesized that P2Y12 inhibitors may improve survival from sepsis by suppressing systemic inflammation and its prothrombotic effects. We therefore determined whether clopidogrel and the novel, more potent P2Y12 inhibitor, ticagrelor, modify these responses in an experimental human model.. We randomized 30 healthy volunteers to ticagrelor (n=10), clopidogrel (n=10), or no antiplatelet medication (controls; n=10). We examined the effect of P2Y12 inhibition on systemic inflammation, which was induced by intravenous injection of Escherichia coli endotoxin. Both P2Y12 inhibitors significantly reduced platelet-monocyte aggregate formation and peak levels of major proinflammatory cytokines, including tumor necrosis factor α, interleukin-6, and chemokine (C-C motif) ligand 2. In contrast to clopidogrel, ticagrelor also significantly reduced peak levels of IL-8 and growth colony-stimulating factor and increased peak levels of the anti-inflammatory cytokine IL-10. In addition, ticagrelor altered leukocyte trafficking. Both P2Y12 inhibitors suppressed D-dimer generation and scanning electron microscopy revealed that ticagrelor also suppressed prothrombotic changes in fibrin clot ultrastructure.. Potent inhibition of multiple inflammatory and prothrombotic mechanisms by P2Y12 inhibitors demonstrates critical importance of platelets as central orchestrators of systemic inflammation induced by bacterial endotoxin. This provides novel mechanistic insight into the lower mortality associated with P2Y12 inhibitors in patients with sepsis in clinical studies.

Topics: Adenosine; Anti-Inflammatory Agents; Biomarkers; Blood Platelets; Chemotaxis, Leukocyte; Clopidogrel; Cytokines; Endotoxins; England; Female; Fibrin Fibrinogen Degradation Products; Humans; Inflammation; Inflammation Mediators; Male; Platelet Adhesiveness; Platelet Aggregation Inhibitors; Prospective Studies; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor; Ticlopidine; Time Factors; Treatment Outcome; Young Adult

Patients with acute coronary syndrome and concomitant atrial fibrillation may require antithrombotic triple therapy but clinical evidence of safety and efficacy is poor. We have therefore studied the combination of different antithrombotic medicines for coagulation activation in an in vivo model in the skin microvasculature.. Platelet activation (β-thromboglobulin [β-TG]) and thrombin generation (prothrombin fragment 1 + 2 [F1+2 ], thrombin-antithrombin complex [TAT]) were studied in an open-label, randomized, parallel group trial in 60 healthy male subjects (n = 20 per group) who received ticagrelor and acetylsalicylic acid (ASA) in combination with dabigatran (150 mg bid), rivaroxaban (20 mg od) or phenprocoumon (INR 2.0-3.0). Coagulation biomarkers in shed blood were assessed at 3 h after monotherapy with the medicines under study, at 3 h after triple therapy dosing and at steady state trough conditions. Single doses of ticagrelor, dabigatran or rivaroxaban caused comparable decreases in shed blood β-TG and were more pronounced than phenprocoumon at an INR of 2.0-3.0. In contrast, thrombin generation was more affected by rivaroxaban and phenprocoumon than by dabigatran. During triple therapy a similarly sustained inhibition of platelet activation and thrombin generation with a maximum decrease of β-TG, F1+2 and TAT at 3 h post-dosing was noted, which remained below pre-dose levels at trough steady state.. A triple therapy at steady state with ticagrelor plus ASA in combination with dabigatran or rivaroxaban is as effective as a combination with phenprocoumon for platelet activation and thrombin generation in vivo.

Topics: Adenosine; Administration, Oral; Adult; Anticoagulants; Antithrombin III; Aspirin; Austria; Benzimidazoles; beta-Alanine; beta-Thromboglobulin; Biomarkers; Blood Coagulation; Blood Platelets; Dabigatran; Drug Therapy, Combination; Fibrinolytic Agents; Healthy Volunteers; Humans; International Normalized Ratio; Male; Morpholines; Peptide Fragments; Peptide Hydrolases; Phenprocoumon; Platelet Activation; Platelet Aggregation Inhibitors; Prospective Studies; Prothrombin; Rivaroxaban; Thiophenes; Thrombin; Thrombosis; Ticagrelor; Young Adult

The aim of this health economic analysis was to compare the cost-effectiveness of ticagrelor versus clopidogrel within the German health care system. A two-part decision model was adapted to compare treatment with ticagrelor or clopidogrel in a low-dose acetylsalicylic acid (ASA) cohort (≤150 mg) for all ACS patients and subtypes NSTEMI/IA and STEMI. A decision-tree approach was chosen for the first year after initial hospitalization based on trial observations from a subgroup of the PLATO study. Subsequent years were estimated by a Markov model. Following a macro-costing approach, costs were based on official tariffs and published literature. Extensive sensitivity analyses were performed to test the robustness of the model. One-year treatment with ticagrelor is associated with an estimated 0.1796 life-years gained (LYG) and gained 0.1570 quality-adjusted life-years (QALY), respectively, over the lifetime horizon. Overall average cost with ticagrelor is estimated to be EUR 11,815 vs. EUR 11,387 with generic clopidogrel over a lifetime horizon. The incremental cost-effectiveness ratio (ICER) was EUR 2,385 per LYG (EUR 2,728 per QALY). Comparing ticagrelor with Plavix(®) or the lowest priced generic clopidogrel, ICER ranges from dominant to EUR 3,118 per LYG (EUR 3,567 per QALY). These findings are robust under various additional sensitivity analyses. Hence, 12 months of ACS treatment using ticagrelor/ASA instead of clopidogrel/ASA may offer a cost-effective therapeutic option, even when the generic price for clopidogrel is employed.

Topics: Acute Coronary Syndrome; Adenosine; Adult; Atherosclerosis; Clopidogrel; Cost-Benefit Analysis; Decision Trees; Double-Blind Method; Drugs, Generic; Follow-Up Studies; Germany; Humans; Markov Chains; Models, Economic; Myocardial Infarction; Platelet Aggregation Inhibitors; Prospective Studies; Quality-Adjusted Life Years; Thrombosis; Ticagrelor; Ticlopidine; Time Factors

Topics: Acute Coronary Syndrome; Adenosine; Clopidogrel; Drug Therapy, Combination; Humans; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Secondary Prevention; Stroke; Thrombosis; Ticagrelor; Ticlopidine; Treatment Outcome

We sought to evaluate the effect of potent platelet inhibition after acute coronary syndrome on total (ie, first and recurrent) occurrences of any of the primary outcome events (e.g., cardiovascular death, myocardial infarction, and stroke) as well as on other ischemic events, such as urgent revascularization, (severe) recurrent ischemia, transient ischemic attacks, and arterial thrombotic events.. In the PLATelet inhibition and patient Outcomes (PLATO) study, 18 624 patients presenting with acute coronary syndromes randomly received ticagrelor (n=9333) or clopidogrel (n=9291). Cox proportional hazard models were used to calculate time to first event and hazard ratios. Total events were compared using a Poisson regression model, and time to second event or death was calculated with the Wei Lin Weissfeld method. Patients randomized to ticagrelor had 1057 total primary end point events versus 1225 for patients on clopidogrel (rate ratio, 0.86; 95% confidence interval, 0.79-0.93; P=0.003). The number of additional events was numerically lower for ticagrelor (189 versus 205; P=0.40), resulting in a hazard for time to second event/death of 0.80 (95% confidence interval, 0.70-0.90; P<0.001) and a number needed to treat of 54. For cardiovascular death/myocardial infarction/stroke/(severe) recurrent ischemia/transient ischemic attack/arterial thrombotic events, total events were fewer with ticagrelor (2030 versus 2290; rate ratio, 0.88; 95% confidence interval, 0.82-0.95; P<0.001), with fewer recurrent events with ticagrelor (740 versus 834; P=0.01) and a highly significant concurrent reduction in hazard for time to second event or death of 0.83 (95% confidence interval, 0.75-0.91; P<0.001). Recurrent PLATO major or Thrombolysis in Myocardial Infarction (TIMI) major non-coronary artery bypass graft bleeding events were infrequent and not different between the two therapies (P=0.96 and 0.38, respectively).. In PLATO, treatment with ticagrelor compared with clopidogrel resulted in a reduction in total events, including first and subsequent recurrent cardiovascular events, when compared with clopidogrel. These types of analyses demonstrate an even greater absolute benefit of ticagrelor over clopidogrel than previously reported.. URL: http://www.clinicaltrials.gov/. Unique identifier: NCT00391872.

Topics: Acute Coronary Syndrome; Adenosine; Aged; Aged, 80 and over; Clopidogrel; Female; Humans; Ischemic Attack, Transient; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Secondary Prevention; Severity of Illness Index; Stroke; Thrombosis; Ticagrelor; Ticlopidine; Treatment Outcome

Habitual smoking has been associated with increased platelet reactivity, increased risk of thrombotic complications and greater efficacy of clopidogrel therapy over placebo. In the PLATO trial, ticagrelor compared to clopidogrel in patients with acute coronary syndromes (ACS) reduced the primary composite end point of vascular death, myocardial infarction and stroke, without increasing overall rates of major bleeding. We evaluated the results in relation to smoking habits.. Interactions between habitual smokers (n = 6678) and in ex/nonsmokers (n = 11,932) and the effects of randomized treatments on ischemic and bleeding outcomes were evaluated by Cox regression analyses.. Habitual smokers had an overall lower risk profile and more often ST-elevation ACS. After adjustment for baseline imbalances, habitual smoking was associated with a higher incidence of definite stent thrombosis (adjusted HR, 1.44 [95% CI, 1.07-1.94]); there were no significant associations with other ischemic or bleeding end points. The effects of ticagrelor compared to clopidogrel were consistent for all outcomes regardless of smoking status. Thus, there was a similar reduction in the primary composite end point for habitual smokers (adjusted HR, 0.83 [95% CI, 0.68-1.00]) and ex/nonsmokers (adjusted HR, 0.89 [95% CI, 0.79-1.00]) (interaction P = .50), and in definite stent thrombosis for habitual smokers (adjusted HR, 0.59 [0.39-0.91]) and ex/nonsmokers (adjusted HR, 0.69 [95% CI, 0.45-1.07]) (interaction P = .61).. In patients hospitalized with ACS, habitual smoking is associated with a greater risk of subsequent stent thrombosis. The reduction of vascular death, myocardial infarction, stroke, and stent thrombosis by ticagrelor compared to clopidogrel is consistent regardless of smoking habits.

Topics: Acute Coronary Syndrome; Adenosine; Aged; Clopidogrel; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Risk Factors; Smoking; Stents; Thrombosis; Ticagrelor; Ticlopidine; Treatment Outcome

During long-term antiplatelet agents (APAs) administration, patients with thrombotic diseases take a fairly high risk of life-threatening bleeding, especially when in need of urgent surgery. Rapid functional reversal of APAs remains an issue yet to be efficiently resolved by far due to the lack of any specific reversal agent in the clinic, which greatly restricts the use of APAs.. Flow cytometry analysis was first applied to assess the dose-dependent reversal activity of platelet-mimicking perfluorocarbon-based nanosponges (PLT-PFCs) toward ticagrelor. The tail bleeding time of mice treated with APAs followed by PLT-PFCs was recorded at different time points, along with corresponding pharmacokinetic analysis of ticagrelor and tirofiban. A hemorrhagic transformation model was established in experimental stroke mice with thrombolytic/antiplatelet therapy. Magnetic resonance imaging was subsequently applied to observe hemorrhage and thrombosis in vivo. Further evaluation of the spontaneous clot formation activity of PLT-PFCs was achieved by clot retraction assay in vitro.. PLT-PFCs potently reversed the antiplatelet effect of APAs by competitively binding with APAs. PLT-PFCs showed high binding affinity comparable to fresh platelets in vitro with first-line APAs, ticagrelor and tirofiban, and efficiently reversed their function in both tail bleeding and postischemic-reperfusion models. Moreover, the deficiency of platelet intrinsic thrombotic activity diminished the risk of thrombogenesis.. This study demonstrated the safety and effectiveness of platelet-mimicking nanosponges in ameliorating the bleeding risk of different APAs, which offers a promising strategy for the management of bleeding complications induced by antiplatelet therapy.

Topics: Animals; Blood Platelets; Hemorrhage; Mice; Platelet Aggregation Inhibitors; Thrombosis; Ticagrelor; Tirofiban

Pharmacological inhibition of the platelet ADP-receptor P2Y

Topics: Acute Coronary Syndrome; Blood Platelets; Fibrinolytic Agents; Humans; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor

We investigated whether combination of glenzocimab, a GPVI inhibitor, with aspirin and ticagrelor provides additional antithrombotic effects, as GPVI has a critical role in atherothrombosis but minimal involvement in hemostasis.. We investigated the effects of glenzocimab (monoclonal antibody Fab fragment) using blood from healthy donors and patients with acute coronary syndrome treated with aspirin and ticagrelor. Platelets were stimulated with multiple agonists, including atherosclerotic plaque, from patients undergoing carotid endarterectomy.. Aspirin and ticagrelor partially inhibited atherosclerotic plaque-induced platelet aggregation by 48% compared with control (34 ± 3 vs 65 ± 4 U; P < .001). Plaque-induced platelet aggregation, adhesion, secretion, and activation were critically dependent on GPVI activation. Glenzocimab alone reduced plaque-induced aggregation by 75% compared with control (16 ± 4 vs 65 ± 4 U; P < .001) and by >95% when combined with aspirin and ticagrelor (3 ± 1 vs 65 ± 4 U; P < .001). Glenzocimab reduced platelet aggregation, adhesion, and thrombin generation when added to blood of aspirin- and ticagrelor-treated patients with acute coronary syndrome. Glenzocimab shared several antithrombotic effects with the GPIIb/IIIa inhibitor eptifibatide with less effect on general hemostasis assessed by rotational thromboelastometry. In a murine intravital model of ST-elevation myocardial infarction, genetic depletion of GPVI reduced microvascular thrombosis.. Addition of glenzocimab to aspirin and ticagrelor enhances platelet inhibition via multiple mechanisms of atherothrombosis. Compared with a GPIIb/IIIa inhibitor, glenzocimab shares multiple antithrombotic effects, with less inhibition of mechanisms involved in general hemostasis.

Topics: Acute Coronary Syndrome; Animals; Aspirin; Fibrinolytic Agents; Humans; Mice; Plaque, Atherosclerotic; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; ST Elevation Myocardial Infarction; Thrombosis; Ticagrelor

Thrombotic cardio-cerebrovascular diseases seriously threaten human health. Currently, conventional thrombolytic treatments are challenged by the low utilization, inferior thrombus penetration, and high off-target bleeding risks of most thrombolytic drugs, resulting in unsatisfactory treatment outcomes. Herein, it is proposed that these challenges can be overcome by precisely integrating the conventional thrombolytic strategy with photothermal therapy. After co-assembly engineering optimization, a fibrin-targeting peptide-decorated nanoassembly of DiR (a photothermal probe) and ticagrelor (TGL, an antiplatelet drug) is prepared for thrombus-homing delivery, abbreviated as FT-DT NPs. The elaborately engineered nanoassembly shows multiple advantages, including simple preparation with high drug co-loading capacity, synchronous delivery of two drugs with long systemic circulation, thrombus-targeted accumulation with self-indicating function, as well as photothermal-potentiated thrombus penetration and thrombolysis with high therapeutic efficacy. As expected, FT-DT NPs not only show bright fluorescence signals in the embolized vessels, but also perform photothermal/antiplatelet synergistic thrombolysis in vivo. This study offers a simple and versatile co-delivery nanoplatform for imaging-guided photothermal/antiplatelet dual-modality thrombolysis.

Topics: Animals; Disease Models, Animal; Drug Delivery Systems; Fibrinolytic Agents; Mice; Nanoparticles; Photothermal Therapy; Platelet Aggregation Inhibitors; Rats; Thrombolytic Therapy; Thrombosis; Ticagrelor

Topics: Animals; Carrageenan; Colchicine; Humans; Male; Mice; Platelet Aggregation Inhibitors; Risk Factors; Thrombosis; Ticagrelor

Activated coagulation factor XI (FXIa) contributes to the development and propagation of thrombosis but plays only a minor role in hemostasis; therefore, it is an attractive antithrombotic target.. To evaluate the pharmacology of asundexian (BAY 2433334), a small molecule inhibitor targeting FXIa, in vitro and in various rabbit models.. The effects of asundexian on FXIa activity, selectivity versus other proteases, plasma thrombin generation, and clotting assays were evaluated. Antithrombotic effects were determined in FeCl. Asundexian inhibited human FXIa with high potency and selectivity. It reduced FXIa activity, thrombin generation triggered by contact activation or low concentrations of tissue factor, and prolonged activated partial thromboplastin time in human, rabbit, and various other species, but not in rodents. In the FeCl. Asundexian is a potent oral FXIa inhibitor with antithrombotic efficacy in arterial and venous thrombosis models in prevention and intervention settings, without increasing bleeding.

Topics: Animals; Anticoagulants; Aspirin; Factor XIa; Fibrinolytic Agents; Hemorrhage; Humans; Platelet Aggregation Inhibitors; Rabbits; Thrombin; Thrombosis; Ticagrelor

Tirofiban has been used historically as a bridge to platelet inhibition with clopidogrel in ST-segment myocardial infarction (STEMI) during percutaneous coronary intervention (PCI) to prevent stent thrombosis. However, ticagrelor and prasugrel reach similar levels of platelet inhibition at 30 minutes to that of clopidogrel at 6 hours, challenging the need for long-duration tirofiban. This 1-year, retrospective cohort study compared ischemic and bleeding outcomes of short-duration versus long-duration tirofiban regimens in patients with STEMI who received ticagrelor or prasugrel at the time of PCI. The primary outcome was major adverse cardiovascular events (MACEs) including cardiovascular mortality, recurrent myocardial infarction, urgent target vessel revascularization, or stroke. Secondary outcomes included individual MACE, all-cause mortality, bleeding events defined by the International Society on Thrombosis and Hemostasis, thirty-day readmissions for MACE and bleeding, and tirofiban pharmacy cost. A total of 283 charts were reviewed and 177 included (short duration n = 57; long duration n = 120). MACE rates were similar between short-duration and long-duration groups (0 [0%] vs. 5 [4.2%]; P = 0.18), including 4 cardiovascular deaths and 1 recurrent myocardial infarction. Bleeding event rates were also similar in short-duration versus long-duration groups including major bleeds (2 [3.5%] vs. 2 [1.7%]; P = 0.60) and clinically relevant nonmajor bleeds (3 [5.3%] vs. 9 [7.5%]; P = 0.75). Cost analysis indicated lower pharmacy cost with the short-duration group. In this cohort of patients with STEMI receiving a fast-acting P2Y12 inhibitor, the length of tirofiban infusion did not affect ischemic or bleeding outcomes, yet short-duration regimens were lower cost.

Topics: Clopidogrel; Hemorrhage; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Retrospective Studies; ST Elevation Myocardial Infarction; Thrombosis; Ticagrelor; Tirofiban; Treatment Outcome

Blood purification therapy is widely used in patients with renal insufficiency and severe infections, where membrane-associated thrombosis is a side effect. How to improve the hemocompatibility of dialysis membranes and reduce thrombosis is a focus of current research, in which platelets play a key role. However, few dialysis membranes that directly inhibit platelets have been developed to date. In this study, a polyethersulfone (PES) membrane was modified with ticagrelor, a platelet P2Y

Topics: Animals; Blood Platelets; Humans; Membranes, Artificial; Platelet Aggregation Inhibitors; Polymers; Renal Dialysis; Sulfones; Thrombosis; Ticagrelor

There are limited data on the outcomes of percutaneous coronary intervention (PCI) following stent thrombosis (ST) and differences exist based on timing.. Our aim was to study the rates of PCI procedures for an ST indication among all patients admitted for PCI at a national level and to compare their characteristics and procedural outcomes based on ST timing.. All PCI procedures in England and Wales (2014-2020) were retrospectively analysed and stratified by the presence of ST into four groups: non-ST, early ST (0-30 days), late ST (>30-360 days), very late ST (>360 days). Multivariable logistic regression models were performed to assess the odds ratios (OR) of in-hospital MACCE (major adverse cardiovascular and cerebrovascular events, a composite of mortality, acute stroke and reinfarction) and mortality.. Overall, 7,923 (1.4%) procedures were for ST indication, most commonly for early ST (n=4,171; 52.6%), followed by very late ST (n=2,801; 35.4%) and late ST (n=951; 12.0%). The rate of PCI for ST declined between 2014 and 2020 (1.7 to 1.4%; p<0.001). Early ST was the only subgroup associated with increased odds of MACCE (OR 1.22, 95% CI: 1.05-1.41), all-cause mortality (OR 1.21, 95% CI: 1.07-1.36) and reinfarction (OR 2.48, 95% CI: 1.48-4.14), compared with non-ST indication. The odds of mortality were significantly reduced in ST patients with the use of intravascular imaging (OR 0.66, 95% CI: 0.48-0.92) and newer P2Y. PCI for ST has declined in frequency over a 7-year period, with most procedures performed for early ST. Among the different times of ST onset, only early ST is associated with worse clinical outcomes after PCI. Routine use of intravascular imaging and newer P2Y

Topics: Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Retrospective Studies; Stents; Thrombosis; Ticagrelor; Treatment Outcome

New antithrombotic medications with less effect on haemostasis are needed for the long-term treatment of acute coronary syndromes (ACS). The platelet receptor glycoprotein VI (GPVI) is critical in atherothrombosis, mediating platelet activation at atherosclerotic plaque. The inhibition of spleen tyrosine kinase (Syk) has been shown to block GPVI-mediated platelet function. The aim of our study was to investigate if the Syk inhibitor fostamatinib could be repurposed as an antiplatelet drug, either alone or in combination with conventional antiplatelet therapy. The effect of the active metabolite of fostamatinib (R406) was assessed on platelet activation and function induced by atherosclerotic plaque and a range of agonists in the presence and absence of the commonly used antiplatelet agents aspirin and ticagrelor. The effects were determined ex vivo using blood from healthy volunteers and aspirin- and ticagrelor-treated patients with ACS. Fostamatinib was also assessed in murine models of thrombosis. R406 mildly inhibited platelet responses induced by atherosclerotic plaque homogenate, likely due to GPVI inhibition. The anti-GPVI effects of R406 were amplified by the commonly-used antiplatelet medications aspirin and ticagrelor; however, the effects of R406 were concentration-dependent and diminished in the presence of plasma proteins, which may explain why fostamatinib did not significantly inhibit thrombosis in murine models. For the first time, we demonstrate that the Syk inhibitor R406 provides mild inhibition of platelet responses induced by atherosclerotic plaque and that this is mildly amplified by aspirin and ticagrelor.

Topics: Aminopyridines; Animals; Aspirin; Fibrinolytic Agents; Humans; Mice; Morpholines; Oxazines; Plaque, Atherosclerotic; Platelet Aggregation Inhibitors; Pyridines; Pyrimidines; Thrombosis; Ticagrelor

Inflammation increases the risk of thrombosis in coronary artery disease (CAD) patients and affects the antiplatelet efficacy of clopidogrel. C1q interacts with platelets to activate platelets and induce thrombosis by participating in and regulating the inflammatory response. Whether C1q affects adenosine diphosphate (ADP)-induced platelet reactivity during clopidogrel therapy was unclear and our study aimed to explore the issue.. We enrolled 1,334 CAD patients receiving clopidogrel therapy and evaluated the association between C1q level and high residual platelet reactivity (HRPR) using logistic regression and restricted cubic spline (RCS). HRPR was defined as ADP-induced maximum amplitude (MA. A total of 516 patients (38.7%) performed HRPR. The frequency of HRPR increases with the increase in C1q level (26.3%, 38.4%, 43.2%, and 46.7% for the 1st to 4th quartile of C1q). The result of multivariate logistic regression demonstrated elevated C1q as an independent predictor for HRPR (2. The current research is the first to explore the association of C1q and ADP-induced platelet reactivity and to demonstrate elevated C1q as an independent risk factor for HRPR in CAD patients during clopidogrel therapy.

Topics: Adenosine; Adenosine Diphosphate; Clopidogrel; Complement C1q; Coronary Artery Disease; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Thrombosis; Ticagrelor; Ticlopidine

A 41-year-old woman with chest pain for 6 hours was admitted to our chest pain center, presenting with acute myocardial infarction. Coronary angiography showed acute total occlusion in the proximal left anterior descending artery due to late stent thrombosis. After thrombus aspiration and intracoronary administration of 0.5 mg tirofiban, repeated angiography showed that no obvious residual stenosis remained. The patient underwent drug-coated balloon angioplasty 69 days ago and was then administered dual antiplatelet treatment (aspirin and clopidogrel) uninterruptedly. Genetic testing found that both cytochrome P450 2C19 (CYP2C19) (G681A) and glycoprotein Ia (GPIa) (C807T, G873A) were hybrid mutant types, demonstrating that the patient was possibly resistant to clopidogrel and aspirin simultaneously. Thus, clopidogrel was replaced by ticagrelor and no more cardiovascular adverse events occurred during the 2-year follow-up.

Topics: Acute Disease; Adult; Aftercare; Angioplasty, Balloon, Coronary; Aspirin; Clopidogrel; Coronary Angiography; Coronary Occlusion; Coronary Restenosis; Cytochrome P-450 CYP2C19; Dual Anti-Platelet Therapy; Female; Fibrinolytic Agents; Humans; Integrin alpha2; Mutation; Myocardial Infarction; Purinergic P2Y Receptor Antagonists; Stents; Thrombectomy; Thrombosis; Ticagrelor; Tirofiban; Treatment Outcome

Thromboses that form in the pedicle after free flap and/or replantation may result in the loss of the flap and/or limb. Ticagrelor is an adenosine diphosphate (ADP) receptor antagonist antithrombotic that can inhibit ADP-dependent platelet activation and aggregation. It is clinically used in acute coronary syndrome and unstable angina. However, its effect on microarterial anastomoses has not been investigated in the literature. An experimental thrombosis model was developed in both femoral arteries of a total of 40 rats. Twenty rats were randomly selected as the drug-free control group, and 20 rats were randomly selected as the ticagrelor group. The rats in the ticagrelor group were administered a 20 mg/kg loading dose orally by gavage 24 h before the experiment, and a maintenance dose of 2x10 mg/kg ticagrelor for 14 days after surgery. After the experiment, the femoral artery was evaluated for macroscopic and microscopic thrombosis, inflammation, edema, and endothelialization. Macroscopically and microscopically, thrombosis was observed at rates of 73.3% and 33.3% in the control group and the ticagrelor group, respectively. Inflammation in the vessel wall was found as 56.7% in the control group and 16.7% in the ticagrelor group. Edema in the vessel wall was found in 63.3% of the control group and 20% of the ticagrelor group. A statistical difference was found between the two groups in terms of thrombosis, inflammation, and edema. Both groups had similar characteristics in terms of endothelialization. Ticagrelor has a reducing effect on thrombosis in the microarterial tuck model.

Topics: Adenosine; Animals; Clopidogrel; Models, Theoretical; Platelet Aggregation Inhibitors; Rats; Thrombosis; Ticagrelor; Ticlopidine

A 65-year-old man developed 3-vessel stent thrombosis after percutaneous coronary intervention with aspirin and clopidogrel. Platelet tests revealed clopidogrel resistance, which resolved after changing clopidogrel to ticagrelor. Although routine platelet tests after stenting are not recommended, these tests may be considered to identify the cause of stent thrombosis and modify antiplatelet therapy.

Topics: Aged; Aspirin; Clopidogrel; Coronary Angiography; Dual Anti-Platelet Therapy; Humans; Male; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Stents; Thrombosis; Ticagrelor

Management of patients treated with Ticagrelor is challenging, as stopping Ticagrelor prior to coronary bypass graft surgery (CABG) may increase the risk of acute stent thrombosis. The aim of the study was to compare bleeding complications in patients treated with ticagrelor combined with acetylsalicylic acid (ASA) versus ASA alone until 1 day before surgery.. Bleeding complications, defined as the composite of red blood cell transfusion ≥1000 ml, chest drainage ≥2000 ml, and bleeding requiring surgical re-exploration, were compared in 161 patients, with 101 on preoperative acetylsalicylic acid (ASA) alone (group A) and 65 on ticagrelor + ASA (group B).. There were no differences in bleeding complications between the two groups (26% vs. 27% in group A and B, respectively), with similar chest drainage in the first 24 h (569 ± 393 ml and 649 ± 427 ml, respectively).. Continuing ticagrelor until coronary artery bypass surgery was not associated with increased bleeding complications, suggesting that continued management with ticagrelor until surgery may be safe.

Topics: Aged; Aspirin; Coronary Artery Bypass; Drainage; Drug Therapy, Combination; Erythrocyte Transfusion; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Postoperative Hemorrhage; Retrospective Studies; Stents; Thoracic Cavity; Thrombosis; Ticagrelor

Topics: Clopidogrel; Humans; Percutaneous Coronary Intervention; Prasugrel Hydrochloride; Prescriptions; Purinergic P2Y Receptor Antagonists; Registries; Stents; Thrombosis; Ticagrelor

Dual antiplatelet therapy (DAPT) remains the cornerstone management for the prevention of acute stent thrombosis after percutaneous intervention (PCI). Situations mandating early interruption of DAPT carry a high risk of ischemic complications. Perioperative bridge therapy using Cangrelor, an intravenous P2Y2 inhibitor, may offer a potential solution. Unfortunately, evidence for its use in non-cardiac procedures is limited.. Our protocol demonstrates successful off-label use of IV Cangrelor bridge therapy in a non-cardiac surgery patient. We describe a case of a 77-year old male; triple therapy with Aspirin, Apixaban, and Ticagrelor for recent drug-eluting stent placement required immediate surgical resection of stage I colonic adenocarcinoma.. Cangrelor bridge therapy was utilized both preoperatively and postoperatively without ischemic or bleeding complications. The patient tolerated exploratory laparoscopic colectomy with minimal bleeding and good post-op recovery.. Minimizing the interruption of DAPT therapy in high-risk patients is achievable. However, careful planning with a team-based approach involving surgeons, cardiologists and pharmacists, along with close clinical follow-up and vigilant management of anti-platelet therapy is recommended.

Topics: Adenosine Monophosphate; Aged; Aspirin; Colectomy; Colonic Neoplasms; Drug-Eluting Stents; Factor Xa Inhibitors; Humans; Male; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Pyrazoles; Pyridones; Thrombosis; Ticagrelor

High on treatment platelet reactivity (HPR) during treatment with clopidogrel has been consistently found to be strong risk factor for recurrent ischemic events after percutaneous coronary intervention (PCI). Insufficient P2Y12 receptor inhibition contributes to HPR measured by the VerifyNow (VN) assay. Prasugrel and ticagrelor are more potent P2Y12 inhibitors than clopidogrel and commonly substituted for clopidogrel when HPR is documented, however benefit of VN guided intensified antiplatelet therapy is uncertain. We identified patients who had undergone platelet reactivity testing after PCI with VN after pretreatment with clopidogrel (n = 252) in a single center observational analysis. Patients who had HPR defined as PRU > 208 were switched to alternate P2Y12 inhibitors. Primary clinical endpoint was 1-year post PCI combined cardiovascular death, myocardial infarction (MI), and stent thrombosis. One hundred and eight (43%) subjects had HPR and were switched to prasugrel (n = 60) and ticagrelor (n = 48). Risk of recurrent 1-year primary endpoint remained higher for HPR patients switched to either ticagrelor or prasugrel as compared to subjects who had low on treatment platelet reactivity (n = 144) (LPR) on clopidogrel [Hazard Ratio: 3.5 (95% CI 1.1-11.1); p = 0.036)]. Propensity score matched analysis demonstrated higher event rates in patients with HPR on alternate P2Y12 inhibitor as compared to patients with LPR (log-rank: p = 0.044). The increased risk of recurrent events associated with HPR measured by VN is not completely attenuated by switching to more potent P2Y12 inhibitors. Non-P2Y12 mediated pathways likely contribute to increased incidence of thrombotic events after PCI in subjects with HPR.

Topics: Aged; Blood Platelets; Clopidogrel; Female; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Activation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Retrospective Studies; Thrombosis; Ticagrelor

Bypass graft surgery remains to be an important treatment option for left main and multivessel coronary artery disease. Approximately 2% of saphenous vein grafts are lost immediately after the coronary artery bypass graft operations and 12% in the first month due to thrombosis.. To administer one anticoagulant and two antiplatelet agents in a way that locally affects the vein graft before the bypass operation and to thereby analyse their effects on early graft thrombosis.. Animal experimentation.. Since ticagrelor was used locally for the first time in this study, its efficacy in combination with other drugs (acetylsalicylic acid, acetylsalicylic acid and ticagrelor, and acetylsalicylic acid + ticagrelor + unfractionated heparin) was examined on rats including control (untreated) and sham (pluronic gel) group (n=14 for each group). Before the tunica adventitia layer of the femoral veins was bypassed to the femoral artery, it was coated with the drug-eluting pluronic F-127 gel. The presence or absence of thrombus in the vein graft samples was recorded under light microscopy. In vein graft preparations where thrombus was detected, the thrombus area (μm. Locally effective acetylsalicylic acid-ticagrelor-unfractionated heparin complex has been shown to significantly reduce thrombus formation in vein grafts in this experimental model. Local administration of these drugs, which are routinely administered orally just before stent implantations, on the vein graft before the bypass is performed can prevent the loss of vein grafts due to thrombus, thereby reducing the mortality and morbidity of these patients.

Topics: Animals; Anticoagulants; Aspirin; Coronary Artery Bypass; Disease Models, Animal; Graft Enhancement, Immunologic; Heparin; Pathology; Platelet Aggregation Inhibitors; Poloxamer; Rats; Thrombosis; Ticagrelor; Veins

Topics: Aged; Aspirin; Bacteria; Case-Control Studies; Dual Anti-Platelet Therapy; Female; Gastrointestinal Microbiome; Humans; Intestines; Male; Methylamines; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Recurrence; Risk Assessment; Risk Factors; Secondary Prevention; Stroke; Thrombosis; Ticagrelor; Time Factors; Treatment Outcome; United States; Up-Regulation

Topics: Antigens, Human Platelet; Arginine; Aspirin; Autoantibodies; Combined Modality Therapy; Coronary Thrombosis; Drug Substitution; Drug Therapy, Combination; Eptifibatide; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Pipecolic Acids; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Platelet Transfusion; Purpura, Thrombocytopenic, Idiopathic; Shock, Cardiogenic; ST Elevation Myocardial Infarction; Stents; Sulfonamides; Thrombectomy; Thrombolytic Therapy; Thrombosis; Ticagrelor; Warfarin

 For patients treated with dual antiplatelet therapy, standardized drug-specific 3-to-7 day cessation is recommended prior to major surgery to reach sufficient platelet function recovery. Here we investigated the hypothesis that supplemental fibrinogen might mitigate the inhibitory effects of antiplatelet therapy..  To this end blood from healthy donors was treated in vitro with platelet inhibitors, and in vitro thrombus formation and platelet activation were assessed. Ticagrelor, acetylsalicylic acid, the combination of both, and tirofiban all markedly attenuated the formation of adherent thrombi, when whole blood was perfused through collagen-coated microchannels at physiological shear rates. Addition of fibrinogen restored in vitro thrombus formation in the presence of antiplatelet drugs and heparin. However, platelet activation, as investigated in assays of P-selectin expression and calcium flux, was not altered by fibrinogen supplementation. Most importantly, fibrinogen was able to restore in vitro thrombogenesis in patients on maintenance dual antiplatelet therapy after percutaneous coronary intervention..  Thus, our in vitro data support the notion that supplementation of fibrinogen influences the perioperative hemostasis in patients undergoing surgery during antiplatelet therapy by promoting thrombogenesis without significantly interfering with platelet activation.

Topics: Aged; Aspirin; Calcium Signaling; Female; Fibrinogen; Hemorheology; Heparin; Hirudins; Humans; In Vitro Techniques; Male; Middle Aged; P-Selectin; Platelet Activation; Platelet Aggregation Inhibitors; Thrombosis; Ticagrelor; Tirofiban

The optimum antithrombotic strategy before open heart surgery in patients with recently implanted coronary stents has not been clearly established because of lack of clinical evidence. This report describes a case of stent thrombosis in a patient who discontinued a P2Y

Topics: Aged; Coronary Artery Bypass; Humans; Male; Platelet Aggregation Inhibitors; Postoperative Complications; Stents; Thrombosis; Ticagrelor; Time Factors; Withholding Treatment

There is little evidence on rates of stent thrombosis (ST) in patients receiving dual antiplatelet therapy (DAPT) with ticagrelor or prasugrel. The aim of this study was to analyze the incidence and predictors of ST after an acute coronary syndrome among patients receiving DAPT with ticagrelor vs prasugrel.. We used data from the RENAMI registry (REgistry of New Antiplatelet therapy in patients with acute Myocardial Infarction), analyzing a total of 4123 acute coronary syndrome patients discharged with DAPT with ticagrelor or prasugrel in 11 centers in 6 European countries. The endpoint was definite ST within the first year. A competitive risk analysis was carried out using a Fine and Gray regression model, with death being the competitive event.. A total of 2604 patients received DAPT with ticagrelor and 1519 with prasugrel; ST occurred in 41 patients (1.10%), with a similar cumulative incidence between ticagrelor (1.21%) and prasugrel (0.90%). The independent predictors of ST were age (sHR, 1.03; 95%CI, 1.01-1.06), ST segment elevation (sHR, 2.24; 95%CI, 1.22-4.14), previous myocardial infarction (sHR, 2.56; 95%CI, 1.19-5.49), and serum creatinine (sHR, 1.29; 95%CI, 1.08-1.54).. Stent thrombosis is infrequent in patients receiving DAPT with ticagrelor or prasugrel. The variables associated with an increased risk of ST were advanced age, ST segment elevation, previous myocardial infarction, and serum creatinine.

Topics: Absorbable Implants; Acute Coronary Syndrome; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Incidence; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prosthesis Failure; Retrospective Studies; Stents; Thrombosis; Ticagrelor

The safety and efficacy of prasugrel and ticagrelor in patients with diabetes mellitus presenting with acute coronary syndrome and treated with percutaneous coronary intervention remain to be assessed.. All diabetes patients admitted for acute coronary syndrome and enrolled in the REgistry of New Antiplatelets in patients with Myocardial Infarction (RENAMI) were compared before and after propensity score matching. Net adverse cardiovascular events (composite of death, stroke, myocardial infarction and BARC 3-5 bleedings) and major adverse cardiovascular events (composite of death, stroke and myocardial infarction) were the co-primary endpoints. Single components of primary endpoints were secondary endpoints.. Among 4424 patients enrolled in RENAMI, 462 and 862 diabetes patients treated with prasugrel and ticagrelor, respectively, were considered. After propensity score matching, 386 patients from each group were selected. At 19±5 months, major adverse cardiovascular events and net adverse cardiovascular events were similar in the prasugrel and ticagrelor groups (5.4% vs. 3.4%,. Diabetes patients admitted for acute coronary syndrome seem to benefit equally in terms of major adverse cardiovascular events from ticagrelor or prasugrel use. Ticagrelor was associated with a significant reduction in all-cause death and bleedings, without differences in recurrent ischaemic events, which should be confirmed in dedicated randomised controlled trials.

Topics: Acute Coronary Syndrome; Aged; Case-Control Studies; Coronary Angiography; Diabetes Complications; Diabetes Mellitus; Hemorrhage; Hospitalization; Humans; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Propensity Score; Recurrence; Registries; Safety; Stents; Thrombosis; Ticagrelor; Treatment Outcome

Although used routinely to reduce thrombotic events in patients with coronary disease, the effects of P2Y

Topics: Adenosine Monophosphate; Aged; Aspirin; Blood Platelets; Clopidogrel; Coronary Artery Disease; Female; Fibrin Clot Lysis Time; Fibrinolysis; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Thrombosis; Ticagrelor

Pretreatment of patients with ST-elevation myocardial infarction (STEMI) with P2Y12 receptor antagonists is supported by guidelines and is a common practice despite the lack of definite evidence for its benefit.. Using data from the Swedish Coronary Angiography and Angioplasty Registry on procedures between 2005 and 2016, we stratified all patients who underwent primary percutaneous coronary intervention due to STEMI in Sweden by whether or not they were pretreated with P2Y12 receptor antagonists. We investigated associations between pretreatment with P2Y12 receptor antagonists and the risk of adverse outcomes using propensity score-adjusted mixed-effects logistic regression, which accounted for clustering of patients within hospitals. The primary endpoint was all-cause death within 30 days. Secondary endpoints were infarct-related artery (IRA) occlusion, 30-day stent thrombosis, in-hospital bleeding, neurological complications, and cardiogenic shock. In total, 44 804 patients were included. They were treated with clopidogrel (N = 26 136, 58.3%), ticagrelor (N = 15 792, 35.3%), or prasugrel (N = 2352, 5.3%); 37 840 (84.5%) were pretreated, and 30 387 (67.8%) had IRA occlusion. At 30 days, there were 2488 (5.6%) deaths and 267 (0.6%) stent thrombosis. Pretreatment was not associated with better survival at 30 days [odds ratio (OR) 1.08, 95% confidence interval (CI) 0.95-1.24; P = 0.313], reduced IRA occlusion (OR 0.98, 95% CI 0.92-1.05; P = 0.608), decreased stent thrombosis (OR 0.99, 95% CI 0.69-1.43; P = 0.932), higher risk of in-hospital bleeding (OR 1.05, 95% CI 0.89-1.26; P = 0.526), or neurological complications (OR 0.72, 95% CI 0.43-1.21; P = 0.210).. Pretreatment of STEMI patients with P2Y12 receptor antagonists was not associated with improved clinical outcomes.

Topics: Aged; Aged, 80 and over; Angioplasty; Clopidogrel; Coronary Angiography; Female; Hemorrhage; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Percutaneous Coronary Intervention; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Registries; ST Elevation Myocardial Infarction; Stents; Survival Rate; Sweden; Thrombosis; Ticagrelor

The aim of this study is to investigate the impact of ticagrelor as compared to clopidogrel based dual antiplatelet therapy (DAPT) during post-discharge management on the incidence of left ventricular (LV) thrombus in patients with first acute anterior ST elevation myocardial infarction (STEMI).. 641 patients who met the inclusion criteria were divided into two groups based on the receipt of either ticagrelor or clopidogrel based DAPT.. Left ventricular thrombus was detected in 73 (11.4%) patients at the first month echocardiographic examination. Ticagrelor based DAPT was associated with significantly less incidence of LV thrombus when compared to clopidogrel [20 (7.4%) vs 53 (14.0%) OR: 0.50 (0.29-0.86)]. Penalized maximum likelihood estimation (PMLE) logistic regression analyses were performed to fourteen candidate variables for identifying the independent predictors of LV thrombus, ticagrelor (compared with clopidogrel) [OR: 0.53 (0.28-0.96), p = 0.039], body mass index (BMI) [OR: 0.58 (0.44-0.77), p < 0.001], KILLIP class (I vs II-IV) [OR: 0.35 (0.14-0.83), p = 0.017], age [OR: 1.22 (1.08-1.40), p < 0.001], poor postprocedural myocardial blush grade (MBG) [OR: 3.35 (1.32-8.15), p = 0.012] and LVEF predischarge [OR: 0.79 (0.72-0.86), p < 0.001] were found to be associated with LV thrombus.. Our study demonstrated that the incidence of LV trombus was significantly lower with ticagrelor than clopidogrel-based DAPT during postdischarge treatment for anterior STEMI patients.

Topics: Aged; Anterior Wall Myocardial Infarction; Aspirin; Clopidogrel; Coronary Angiography; Dose-Response Relationship, Drug; Dual Anti-Platelet Therapy; Echocardiography; Female; Follow-Up Studies; Heart Diseases; Heart Ventricles; Humans; Incidence; Male; Middle Aged; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Retrospective Studies; ST Elevation Myocardial Infarction; Thrombosis; Ticagrelor; Treatment Outcome; Turkey

Topics: Clopidogrel; Coronary Artery Disease; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; ST Elevation Myocardial Infarction; Stents; Thrombosis; Ticagrelor

Despite great advances with the introduction of ticagrelor and prasugrel in the treatment of acute coronary syndromes (ACS), the risk of thrombosis and bleeding remains significant and affects the choice of clinicians in the treatment of the single patient. Large registries are effective tools to explore patterns of drug administration and adherence to guideline recommendations in real-world clinical practice.. START- antiplatelet is a prospective, observational registry carried out by seven Italian cardiology institutions on patients admitted for ACS aimed to document the real world treatment of ACS patients, adding also data on 12-month follow-up. We present data on the first 1050 patients who have completed 1-year follow-up on a total of 1537 patients. Primary end-points were: 1) MACCE (Major Adverse Cardiovascular and Cerebrovascular Events) including all-cause and cardiovascular mortality, non fatal MI, urgent revascularization, TIA and ischemic stroke; 2) Major and minor bleeding according to TIMI, GUSTO and ISTH classifications.. The dual antiplatelet treatment most prescribed was aspirin plus ticagrelor (47.9%) and aspirin plus clopidogrel (32.1%). At a mean follow-up was 335±131 days, both ticagrelor and prasugrel are associated with a statistically significant reduced total and cardiovascular mortality. Both prasugrel and ticagrelor do not show a significant increased incidence of major and minor bleedings with respect to clopidogrel. Patients with monotherapy had significantly higher incidence of both ischemic stroke and major bleedings.. The analysis of the register has documented that both ticagrelor and prasugrel are associated with a statistically significant reduced total and cardiovascular mortality but both do not show a significant increased incidence of major and minor bleedings with respect to clopidogrel.

Topics: Acute Coronary Syndrome; Aged; Cardiovascular Diseases; Cerebrovascular Disorders; Female; Follow-Up Studies; Hemorrhage; Humans; Italy; Kaplan-Meier Estimate; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prospective Studies; Registries; Risk; Stroke; Thrombosis; Ticagrelor; Treatment Outcome

Preload with clopidogrel, ticagrelor, or prasugrel in the setting of ST-segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PCI) is frequently applied. Limited data are available regarding the outcome impact of pretreatment with these drugs in the real world.. The outcome of 760 STEMI patients treated by primary PCI receiving clopidogrel, prasugrel, or ticagrelor (n = 269, 327, 164, respectively) was evaluated. Patients in the clopidogrel group were older, whereas those in the ticagrelor group had less hypertension but were more active smokers. Angiographic characteristics were comparable among the three groups. At 1 month, more events were observed in the clopidogrel group (11.1%) than in the ticagrelor and prasugrel groups (7.1 vs. 5.1%, P = 0.025), whereas the number of events in the ticagrelor and prasugrel groups did not differ. At 1 year, similar differences existed, mainly driven by a higher rate of death (19.5%, P = 0.008) or stent thrombosis (2 vs. 1.3% for ticagrelor, P = 0.132; vs. 0.3% for prasugrel, P = 0.07) in the clopidogrel group. In-hospital and 1-year bleeding rates were similar between groups.. In real-world practice, pretreatment with prasugrel or ticagrelor in ongoing STEMI treated by primary PCI seems to be a well tolerated alternative strategy compared with clopidogrel but provides superior benefit in terms of outcomes.

Topics: Aged; Belgium; Clopidogrel; Female; Hemorrhage; Humans; Male; Middle Aged; Multivariate Analysis; Percutaneous Coronary Intervention; Prasugrel Hydrochloride; Preoperative Care; Purinergic P2Y Receptor Antagonists; ST Elevation Myocardial Infarction; Stents; Survival Analysis; Thrombosis; Ticagrelor; Time Factors; Treatment Outcome

This study aimed to explore the effects of ticagrelor (a P2Y12 receptor inhibitor) on interleukin (IL)-17 and myeloperoxidase (MPO) expression in coronary thrombus as well as on the coronary blood flow in ST-segment elevation myocardial infarction (STEMI) patients following percutaneous coronary intervention (PCI).. Forty STEMI patients who were admitted to the First Affiliated Hospital of Harbin Medical University between August 1, 2014 and December 30, 2014 were enrolled in this study according to a set inclusion criteria. They were randomized to ticagrelor and clopidogrel groups and treated with 180 mg ticagrelor and 600 mg clopidogrel before PCI, respectively. Intracoronary thrombus aspiration was performed by a physician during PCI. Immunohistochemistry and Western blot analysis were carried out to detect the expression of IL-17 and MPO in the thrombus. Corrected thrombolysis in myocardial infarction frame count (CTFC) was used to evaluate blood flow after PCI.. Immunohistochemistry results showed that the average positive staining area percentage of IL-17 and MPO in the clopidogrel group was significantly higher than that in the ticagrelor group. Western blot analysis also showed similar results for IL-17 (clopidogrel 0.71 ± 0.036, ticagrelor 0.50 ± 0.56) and MPO (clopidogrel 0.50 ± 0.040; ticagrelor 0.38 ± 0.06). CTFC was lower in the ticagrelor group than that in the clopidogrel group (P < 0.05).. Ticagrelor is more effective than clopidogrel in reducing inflammation thrombosis and improving postprocedural PCI blood flow in STEMI patients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Topics: Adolescent; Adult; Aged; Clopidogrel; Coronary Circulation; Female; Humans; Interleukin-17; Middle Aged; Peroxidase; Platelet Aggregation Inhibitors; ST Elevation Myocardial Infarction; Thrombosis; Ticagrelor; Young Adult

Recurrent thrombotic events still occur despite dual antiplatelet therapy in patient's post percutaneous coronary intervention (PCI) could be attributed to high on-treatment platelet reactivity.. A 44-year-old male, who had staged PCI to left anterior descending (LAD) 2 weeks after an anterior MI, with a drug-coated stent was readmitted with new anterior STEMI 35 days later. Coronary angiogram revealed mid-stent thrombus in situ. He had further uncomplicated PCI. Platelet function testing and genotyping showed clopidogrel high on-treatment platelet reactivity and CYP2C19*3/*17 genotype. Ticagrelor was commenced.. This case study is the first reported in Malaysia to document a patient with a CYP2C19*3/*17 genotype presenting with a stent thrombosis after an uncomplicated index PCI procedure.

Topics: Adult; Blood Platelets; Clopidogrel; Cytochrome P-450 CYP2C19; Drug-Eluting Stents; Genotype; Humans; Male; Platelet Aggregation Inhibitors; Thrombosis; Ticagrelor

Topics: Aspirin; Clopidogrel; Humans; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Thrombosis; Ticagrelor; Tomography, Optical Coherence

Previous studies have identified high on treatment platelet reactivity (HTPR) as a potent factor predicting ischemic events for patients with coronary heart disease. We assessed the efficacy and safety of ticagrelor (90 mg twice-daily) and double-dose of clopidogrel (150 mg once-daily) among Chinese patients for elective percutaneous coronary intervention. We enrolled 40 patients with HTPR from among 317 patients with non-ST-segment elevation acute coronary syndromes after a successful elective percutaneous coronary intervention (PCI). Platelet reactivity was measured by VerifyNow P2Y12 assay. Platelet reactivity was significantly lower for both groups when compared with baseline platelet reactivity after medication adjustment (all P < 0.001). The mean platelet reactivity units (PRU) was significantly lower for the ticagrelor group compared with that of the clopidogrel group over time (all P < 0.001). The differences in the rate of sustained HTPR at different time points between the two groups were significant (2 hours: 0% versus 60%; 8 hours: 5.6% versus 50%; 24 hours: 5.9% versus 43.8%, all P < 0.05). Genetic variation of CYP2C19*2 had no impact on PRU means or rate of HTPR in the ticagrelor group (P > 0.05). During the 30-day follow-up, no MACE occurred in any patient, and the overall risk of bleeding showed no difference between the two groups (35% versus 21%, P = 0.48). Our results suggest that ticagrelor may achieve a more rapid and greater platelet inhibition than double-dose clopidogrel. Further studies are still needed to assess the differences in efficacy and safety between ticagrelor and double-dose clopidogrel administration for Chinese patients post elective PCI.

Topics: Adenosine; Aged; Clopidogrel; Cytochrome P-450 CYP2C19; Female; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Activation; Postoperative Complications; Purinergic P2Y Receptor Antagonists; Thrombosis; Ticagrelor; Ticlopidine

Topics: Adenosine; Aspirin; Clopidogrel; Coronary Vessels; Drug Hypersensitivity; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Recurrence; Stents; Thrombosis; Ticagrelor; Ticlopidine

A 54-year-old man underwent percutaneous coronary intervention (PCI) and two stents were placed on left anterior coronary artery and circumflex artery. Low molecular weight heparin (LMWH) together with ticagrelor 90 mg twice a day and acetylsalicylic acid (Aspirin) were started after PCI due to high risk of stent thrombosis. On the fourth day of patient's follow-up in the intensive care unit (ICU), bloody secretion was started from endotracheal tube. Hemoglobin dropping, bilateral infiltration on the chest X-ray and bleeding from lung were diagnosed as diffuse alveolar hemorrhage (DAH). Apart from LMWH and antiplatelet therapies with aspirin and ticagrelor, there were no other identified risk factors for DAH. As far as we know, our report is the first case of DAH caused by LMWH and dual anti-platelet therapy including ticagrelor.

Topics: Adenosine; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Drug Therapy, Combination; Fatal Outcome; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Pulmonary Alveoli; Purinergic P2Y Receptor Antagonists; Risk Factors; Stents; Thrombosis; Ticagrelor

Definition of the optimal duration of dual anti-platelet therapy (DAPT) is an important clinical issue, given the large number of patients having percutaneous coronary intervention (PCI), the costs and risks of pharmacologic therapy, the consequences of stent thrombosis, and the potential benefits of DAPT in preventing ischaemic outcomes beyond stent thrombosis. Nowadays, the rationale for a prolonged duration of DAPT should be not only the prevention of stent thrombosis, but also the prevention of ischaemic events unrelated to the coronary stenosis treated with index PCI. A higher predisposition to athero-thrombosis may persist for years after an acute myocardial infarction, and even stable patients with a history of prior myocardial infarction are at high risk for major adverse cardiovascular events. Recently, results of pre-specified post-hoc analyses of randomized clinical trials, including the PEGASUS-TIMI 54 trial, have shed light on strategies of DAPT in various clinical situations, and should impact the next rounds of international guidelines, and also routine practice. Accordingly, the 2015 to 2016 the Board of the Italian Society of Cardiology addressed newer recommendations on duration of DAPT based on most recent scientific information. The document states that physicians should decide duration of DAPT on an individual basis, taking into account ischaemic and bleeding risks of any given patient. Indeed, current controversy surrounding optimal duration of DAPT clearly reflects the fact that, nowadays, a one size fits all strategy cannot be reliably applied to patients treated with PCI. Indeed, patients usually have factors for both increased ischaemic and bleeding risks that must be carefully evaluated to assess the benefit/risk ratio of prolonged DAPT. Personalized management of DAPT must be seen as a dynamic prescription with regular re-evaluations of the risk/benefit to the patient according to changes in his/her clinical profile. Also, in order to derive more benefit than harm from new treatments, a multi-parametric approach using several risk scores of the ischaemic and bleeding risks might improve the process of risk factor characterization. In patients with high ischaemic risk, particularly those with a history of myocardial infarction, the benefits of extended DAPT (particularly with ticagrelor up to 3 years) are likely to outweigh the risks.

Topics: Adenosine; Aspirin; Cardiology; Drug Administration Schedule; Drug-Eluting Stents; Hemorrhage; Humans; Italy; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Societies, Medical; Thrombosis; Ticagrelor

Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker has been proven to reduce subsequent cardiovascular events and in-stent thrombosis in patients undergoing percutaneous coronary intervention. Newer P2Y12 antagonists with faster onset and greater inhibition of platelet activity have improved cardiovascular outcomes but have created uncertainty with the appropriate dosing when switching between agents. Currently, there are no evidence-based guidelines to aid clinicians when switching between P2Y12 receptor blockers. Here we describe two patients that developed in-stent thrombosis when switching from ticagrelor to clopidogrel using a 300 mg clopidogrel loading dose. Both patients presented with ST elevation myocardial infarction and underwent stent placement but then developed in-stent thrombosis 48 hours after switching from ticagrelor to clopidogrel. These cases illustrate the severe consequences of suboptimal platelet inhibition and the need for prospective trials thoroughly powered to assess clinical outcomes in order to determine the most appropriate strategy when switching from ticagrelor to clopidogrel.

Topics: Adenosine; Blood Platelets; Clopidogrel; Drug Administration Schedule; Drug Dosage Calculations; Drug Substitution; Female; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Purinergic P2Y Receptor Antagonists; ST Elevation Myocardial Infarction; Stents; Thrombosis; Ticagrelor; Ticlopidine

The P2Y. Ticagrelor, unlike clopidogrel, exhibits endothelial-specific antithrombotic properties and blunts arterial thrombus formation. The additional antithrombotic properties displayed by ticagrelor may explain its greater efficacy in reducing thrombotic events in clinical trials. These findings may provide the basis for new indications for ticagrelor.

Topics: Adenosine; Animals; Blood Coagulation; Blood Platelets; Carotid Artery Injuries; Cells, Cultured; Clopidogrel; Disease Models, Animal; Down-Regulation; Endothelial Cells; Equilibrative Nucleoside Transporter 1; Fibrinolytic Agents; Humans; Male; Mice, Inbred C57BL; Platelet Aggregation Inhibitors; Proteasome Endopeptidase Complex; Proteolysis; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thromboplastin; Thrombosis; Ticagrelor; Ticlopidine; Time Factors; Tumor Necrosis Factor-alpha

Residual high-on treatment platelet reactivity (HRPR) predicts outcomes and major cardiovascular events. Ticagrelor has provided pharmacological and clinical evidence of more predictable and more potent antiplatelet effect as compared to clopidogrel. However, so far, few data have investigated the prevalence and predictors of HRPR in unselected patients treated with ticagrelor, that is therefore the aim of the current study.. Our population is represented by 195 patients undergoing coronary stenting for ACS and receiving ASA and ticagrelor. Platelet function was assessed by multiplate impedance aggregometry (MEA) between 1 and 3months after stenting. Main clinical features and biochemistry parameters were collected. HRPR for ticagrelor was defined for aggregation>417 AUC after MEA-ADP stimulation. A total of 26 patients, (13.3%), displayed HRPR with ticagrelor. Older age (≥70years, p=0.002), hypertension (p=0.02) previous myocardial infarction (p=0.04), therapy with nitrates and beta-blockers (p=0.02), diuretics (p=0.03) and fasting glycaemia (p=0.05) were associated to HRPR with ticagrelor. By multivariate analysis, age≥70years (OR [95%CI]=4.6[1.55-13.8], p=0.006), concomitant therapy with beta-blockers (OR [95%CI]=3.2[1.06-9.6], p=0.04) and platelets count (OR[95%CI]=1.0007 [1-1.016], p=0.05) were identified as independent predictors of HRPR with ticagrelor.. The present study firstly demonstrates that the occurrence of HRPR in patients treated with ticagrelor is not so futile, as it was observed in 13% of patients treated with ticagrelor. Older age, beta-blockers administration and platelets count are independent predictors of HRPR with ticagrelor.

Topics: Acute Coronary Syndrome; Adenosine; Age Factors; Aged; Blood Platelets; Drug Therapy, Combination; Female; Humans; Male; Percutaneous Coronary Intervention; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Predictive Value of Tests; Stents; Thrombosis; Ticagrelor

ESSENTIALS: Dual antiplatelet therapy (DAPT) in elderly patients requires balancing bleedings and thrombosis. Impact of age on high residual on-treatment platelet reactivity (HRPR) on DAPT was studied. A reduced effectiveness of adenosine diphosphate antagonists was observed over 70 years of age. The occurrence of HRPR was increased among elderly patients with both clopidogrel and ticagrelor.. The aim of the present study was to evaluate the impact of age on platelet function and the occurrence of high residual on-treatment platelet reactivity (HRPR) in patients treated with dual antiplatelet therapy (DAPT) using acetylsalicilic acid (ASA) and clopidogrel or ticagrelor.. Patients treated with DAPT (ASA and clopidogrel or ticagrelor) were scheduled for platelet function assessment at 30-90 days post-discharge. By whole blood impedance aggregometry, HRPR was considered for ASPI test values > 862 AU*min (for ASA) and adenosine diphosphate (ADP) test values > 417 AU*min (for ADP antagonists). Elderly patients were defined as those aged ≥ 70 years.. Among 494 patients on DAPT, 224 (45.3%) were ≥ 70 years old. ADP-mediated platelet aggregation increased with decades of age (279.3 ± 148.6 vs. 319.6 ± 171.1 vs. 347.3 ± 190.1 vs. 345.7 ± 169.2), whereas no difference was observed for ASA response. A reduced effectiveness of ADP antagonists was observed among elderly patients; in fact, among the 117 patients displaying HRPR (23.7%), a higher prevalence was observed among patients over 70 years old (30.4% vs. 18.1%; adjusted odds ratio (OR) [95% confidence interval (CI)] = 2.19 [1.29-3.71]). Similar results were obtained among the 266 clopidogrel-treated patients (38.5% vs. 27.9%; adjusted OR [95% CI] = 2.91 [1.46-5.8]) and in the 228 patients receiving ticagrelor (19.1% vs. 8.1%; adjusted OR [95% CI] = 2.55 [1.02-8.59]).. In patients receiving dual antiplatelet therapy, advanced age is independently associated with a reduced effectiveness of ADP antagonists and a higher rate of HRPR with both clopidogrel and ticagrelor.

Topics: Adenosine; Adenosine Diphosphate; Age Factors; Aged; Aged, 80 and over; Aspirin; Blood Platelets; Clopidogrel; Cohort Studies; Female; Humans; Male; Middle Aged; Odds Ratio; Patient Discharge; Percutaneous Coronary Intervention; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prevalence; Thrombosis; Ticagrelor; Ticlopidine; Time Factors

Early stent thrombosis (EST) (≤ 30 days after stent implantation) is a relatively rare but deleterious complication of percutaneous coronary intervention (PCI). Administration of newer P2Y12 inhibitors (prasugrel and ticagrelor) combined with aspirin has been shown to reduce the incidence of sub-acute and late stent thrombosis, compared with clopidogrel. We investigated the "real life" incidence of EST in patients from a large acute coronary syndrome (ACS) national registry, where newer P2Y12 inhibitors are widely used. Patients were derived from the ACS Israeli Survey (ACSIS), conducted during 2006, 2008, 2010 and 2013. Major adverse cardiac events (MACE) at 30days were defined as all-cause death, recurrent ACS, EST and stroke.Of the 4717 ACS patients who underwent PCI and stenting, 83% received clopidogrel and 17% newer P2Y12 inhibitors. The rate of EST was similar in both groups (1.7% in the newer P2Y12 inhibitor group vs. 1.4% in the clopidogrel-treated patients, p = 0.42). Results were consistent after multivariate analysis (adjusted HR = 1.06 [p = 0.89]). MACE occurred in 6.4% in the newer P2Y12 inhibitor group compared with 9.2% in the clopidogrel group (P<0.01). However, multivariate logistic regression modeling showed that treatment with newer P2Y12 inhibitors was not significantly associated with the secondary endpoint of MACE when compared with clopidogrel therapy [OR = 1.26 95%CI (0.93-1.73), P = 0.136]. The incidence of "real life" EST at 1month is relatively low, and appears to be similar in patients who receive newer P2Y12 inhibitors as well as in those who receive clopidogrel.

Topics: Acute Coronary Syndrome; Adenosine; Aged; Aspirin; Clopidogrel; Early Diagnosis; Female; Humans; Israel; Male; Middle Aged; Multivariate Analysis; Percutaneous Coronary Intervention; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Registries; Stents; Stroke; Survival Analysis; Thrombosis; Ticagrelor; Ticlopidine

Topics: Adenosine; Aged; Aspirin; Blood Coagulation; Cardiomyopathies; Clopidogrel; Drug Substitution; Drug Therapy, Combination; Fibrinolytic Agents; Heart-Assist Devices; Humans; Male; Medication Therapy Management; Postoperative Complications; Risk Adjustment; Thrombosis; Ticagrelor; Ticlopidine; Treatment Outcome

three complementary biocatalytic routes were examined for the synthesis of the cyclopropyl amine (1R,2S)-2, which is a key building block for the anti-thrombotic agent ticagrelor 1. By employing either a ketoreductase, amidase or lipase biocatalyst, the key building blocks for synthesis of the amine 2 were obtained in 99.9, 92.5 and 46.3 ee, respectively.

Topics: Adenosine; Amines; Biocatalysis; Chemistry Techniques, Synthetic; Hydrolysis; Thrombosis; Ticagrelor

Treatment with warfarin in combination with clopidogrel has been shown to reduce the incidence of major bleeding as compared to triple antithrombotic therapy (TT; warfarin, clopidogrel and aspirin). However, there are uncertainties regarding the risk for thrombosis since poor-responsiveness to clopidogrel is common. Ticagrelor is a more potent platelet inhibitor, but data supporting concurrent use of ticagrelor and warfarin (dual antithrombotic therapy, DT) is limited. This study therefore sought to evaluate the risk of bleeding and thrombosis associated with DT after an acute coronary syndrome (ACS).. We identified all ACS patients on DT upon discharge from Helsingborg Hospital and Skåne University Hospital in Malmö and Lund, Sweden, during 2013. Patients on DT were compared with historical controls discharged with TT. Major bleeding was defined in accordance with the HAS-BLED derivation study. Patients were retrospectively followed for three months.. In total, 107 DT patients were identified and compared with 159 controls on TT. Mean HAS-BLED bleeding risk score and duration of treatment were similar between the groups (HAS-BLED 2.2+/-0.8 vs 2.2+/-1.0 units, p=NS; duration 2.7+/-0.8 vs 2.5+/-0.9months, p=NS; DT vs TT). The incidence of spontaneous major bleeding was similar between the groups, as was a composite of all thrombotic events, i.e. peripheral embolism, stroke/TIA and acute coronary syndrome (bleeding 8/106 (7.5%) vs 11/157 (7.0%), p=NS; thrombosis 5/106 (4.7%) vs 5/157 (3.2%), p=NS; DT vs TT).. Rates of thrombotic and bleeding events were similar in patients with TT and patients with ticagrelor and warfarin.

Topics: Acute Coronary Syndrome; Adenosine; Aged; Aged, 80 and over; Aspirin; Atrial Fibrillation; Clopidogrel; Drug Therapy, Combination; Female; Fibrinolytic Agents; Hemorrhage; Humans; Male; Middle Aged; Retrospective Studies; Risk Factors; Thrombosis; Ticagrelor; Ticlopidine; Treatment Outcome; Warfarin

Topics: Adenosine; Aspirin; Drug-Eluting Stents; Female; Humans; Male; Piperazines; Platelet Aggregation Inhibitors; Thiophenes; Thrombosis; Ticagrelor; Ticlopidine

Topics: Adenosine; Adult; Aged; Anticoagulants; Aspirin; Drug Therapy, Combination; Heart Failure; Heart-Assist Devices; Heparin; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Prosthesis Design; Thrombosis; Ticagrelor; Treatment Outcome; Ventricular Function, Left

Dual antiplatelet therapy is an established standard of care for patients with acute coronary syndrome (ACS) to reduce thrombotic risk. Reduced CYP2C19 activity impairs clopidogrel bio-activation and increases risk of adverse clinical outcomes. Patients with poor and intermediate CYP2C19 metabolizers treated with clopidogrel incur higher cardiovascular event rates, including myocardial infarction, stroke, and stent thrombosis, following ACS than patients with normal CYP2C19 function. Tests are available to identify the CYP2C19 genotype and can be used to support individualization of antiplatelet therapy. . To estimate the financial impact of CYP2C19 genotyping in a theoretical cohort of 1,000 patients with ACS, who received percutaneous coronary intervention and coronary stent implantation and were treated with clopidogrel, prasugrel, or ticagrelor in a managed care setting. . Differences in overall and average cost per patient were estimated based on the rate of CYP2C19 genotyping in a theoretical cohort of 1,000 patients. Sensitivity analysis was carried out for varying costs, adherence, and the percentage of patients treated according to genotyping results. All clinical event costs were reported in terms of 2012 U.S. dollars. The budget impact analysis used published event rates from primary literature to estimate costs of events analysis for 3 different scenarios: Scenario A, no CYP2C19 genotyping; Scenario B, 50% of patients received CYP2C19 genotyping with appropriate treatment based on genotype; and Scenario C, 100% of patients received CYP2C19 genotyping with appropriate treatment based on genotype. . According to this model, there was no change in the market share for the 3 antiplatelet agents in Scenario A. Initial market share for clopidogrel, prasugrel, and ticagrelor was 93%, 5%, and 2%, respectively; however, use of CYP2C19 genotyping is expected to shift market share from clopidogrel to either prasugrel or ticagrelor. In Scenario B, where 50% of the patients received genotyping, clopidogrel market share was reduced to 83%, while prasugrel increased to 12.1% and ticagrelor increased to 4.9%. In Scenario C, where all patients received genotyping, clopidogrel market share was reduced to 73%, prasugrel increased to 19.3%, and ticagrelor increased to 7.7%. Total estimated cost differences when all possible patients were genotyped included annual savings of roughly $444,852.. Important financial benefits may be realized through use of genotype-guided antiplatelet therapy to reserve prasugrel or ticagrelor use for patients with reduced CYP2C19 activity to avoid costs associated with adverse cardiac events.

Topics: Acute Coronary Syndrome; Adenosine; Clopidogrel; Cytochrome P-450 CYP2C19; Drug Therapy, Combination; Genetic Testing; Genotype; Humans; Managed Care Programs; Models, Economic; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thrombosis; Ticagrelor; Ticlopidine

A 55-year-old man presented with acute ST-elevation myocardial infarction. He received rescue angioplasty with one drug eluting stent. He developed marked breathlessness and haemoptysis two days later. Investigations led to the diagnosis of pulmonary haemorrhage, possibly from pneumonitis caused by ticagrelor. He was successfully managed with high-dose steroids and ticagrelor was replaced with clopidogrel. On stopping the steroids a month later, mild haemoptysis recurred and this was managed conservatively. Pneumonitis and pulmonary haemorrhage is rarely reported with acute myocardial infarction, but poses serious challenge to the patient and the clinician. Diagnosis may be delayed as breathlessness can occur due to myriad causes after myocardial infarction. Interrupting dual anti-platelet therapy after angioplasty could lead to devastating stent thrombosis.

Topics: Adenosine; Angioplasty; Hemoptysis; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Pneumonia; Purinergic P2Y Receptor Antagonists; Radiography, Thoracic; Thrombosis; Ticagrelor

In the search of a potential backup for clopidogrel, we have initiated a HTS campaign designed to identify novel reversible P2Y12 antagonists. Starting from a hit with low micromolar binding activity, we report here the main steps of the optimization process leading to the identification of the preclinical candidate SAR216471. It is a potent, highly selective, and reversible P2Y12 receptor antagonist and by far the most potent inhibitor of ADP-induced platelet aggregation among the P2Y12 antagonists described in the literature. SAR216471 displays potent in vivo antiplatelet and antithrombotic activities and has the potential to differentiate from other antiplatelet agents.

Topics: Acute Coronary Syndrome; Adenosine Diphosphate; Administration, Oral; Animals; Binding, Competitive; CHO Cells; Cricetinae; Cricetulus; Humans; Indoles; Injections, Intravenous; Male; Models, Chemical; Molecular Structure; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Pyridazines; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2Y12; Thrombosis

Prasugrel is a widely used antiplatelet agent in the setting of percutaneous coronary intervention. In case of resistance to this third-generation thienopyridine, choices of alternative drugs remain limited. Here, we describe a case of a 49-year-old man with stent thrombosis occurring 5 days after drug-eluting stent implantation despite a well-conducted antiplatelet therapy with aspirin and prasugrel. Evaluation of platelet functions by different tests revealed prasugrel resistance. Genotyping for various CYP single-nucleotide polymorphisms showed that the patient carried mutant alleles encoding enzymes CYP2B6 and CYP2C9 involved in prasugrel metabolic pathway. Strikingly, an adequate platelet response was rapidly obtained after switching from prasugrel to ticagrelor.

Topics: Adenosine; Drug Resistance; Humans; Male; Middle Aged; Piperazines; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Thiophenes; Thrombosis; Ticagrelor

P2Y(12) receptor antagonism inhibits platelet aggregation by preventing adenosine diphosphate (ADP)-mediated amplification of activation pathways downstream of primary agonists, such as thrombin and collagen. However, the role of ADP signaling in maintaining aggregate stability and the effects of P2Y(12) antagonists on preestablished aggregates in vitro and arterial thrombus in vivo are not well understood. This study evaluated the impact of P2Y(12) signaling on platelet aggregate stability and early thrombotic occlusion using a reversible P2Y(12) antagonist, ticagrelor. There were 2 study objectives: (1) to determine if there was a time-dependent factor on the capacity of a P2Y(12) antagonist to affect human platelet aggregate stability in vitro using light transmission aggregometry and (2) to evaluate the extent of arterial thrombus reversal in a preclinical model upon administration of ticagrelor in vivo. Platelet aggregates were exposed to ticagrelor after ADP or collagen activation, monitored for stability by aggregometry, and visualized by microscopy. Freshly formed ADP- and collagen-induced platelet aggregates were more rapidly dispersed by a P2Y(12) antagonist than drug carrier control at clinically relevant concentrations (P < 0.05). However, stable aggregates were not noticeably affected. A murine arterial thrombosis model was used to evaluate thrombus stability in an in vivo mouse model. Thrombotic occlusion was induced by FeCl(3), followed by a bolus intravenous administration of ticagrelor or vehicle control. Doppler blood flow was monitored before injury and 30 minutes after bolus administration. Arteries were retrieved for inspection for residual thrombus. Early arterial thrombotic occlusion in vivo was partially reversed by ticagrelor administration. Blood flow through the injured artery increased, and thrombus size within the artery decreased (P < 0.05, n = 3). In conclusion, P2Y(12) antagonism disrupts the stability of newly formed platelet aggregates, promoting disaggregation, and reverses thrombotic vascular occlusion. Thus, in addition to activating platelets, signaling via P2Y(12) seems to be required for stabilizing platelet thrombi.

Topics: Adenosine; Animals; Humans; Male; Mice; Mice, Inbred C57BL; Platelet Aggregation; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Signal Transduction; Thrombosis; Ticagrelor; Time Factors

Topics: Acute Coronary Syndrome; Adenosine; Female; Follow-Up Studies; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Piperazines; Postoperative Care; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Recurrence; Retrospective Studies; Thiophenes; Thrombosis; Ticagrelor

Topics: Adenosine; Aged; Clopidogrel; Drug Substitution; Dyspnea; Humans; Male; Purinergic P2Y Receptor Antagonists; Stents; Thrombosis; Ticagrelor; Ticlopidine

The ATLANTIC trial compared effects of initiation of ticagrelor at the prehospital (ambulance) or hospital (in the catheterization laboratory) stage of treatment of patients with ST-segment elevation myocardial infarction. Initiation of therapy with ticagrelor at prehospital stage short before percutaneous coronary intervention was safe, but did not improve coronary reperfusion before this procedure. However, earlier administration of ticagrelor significantly reduced the risk of stent thrombosis after percutaneous coronary intervention.

Topics: Adenosine; Coronary Circulation; Emergency Medical Services; Female; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Complications; Preoperative Care; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Stents; Thrombosis; Ticagrelor; Time-to-Treatment; Treatment Outcome

Synthesis and structure-activity relationships of ethyl 6-aminonicotinate acyl sulfonamides, which are potent antagonists of the P2Y12 receptor, are presented. Shifting from 5-chlorothienyl to benzyl sulfonamides significantly increased the potency in the residual platelet count assay. Evaluation of PK parameters in vivo in dog for six compounds showed a 10-fold higher clearance for the azetidines than for the matched-pair piperidines. In a modified Folts model in dog, both piperidine 3 and azetidine 13 dose-dependently induced increases in blood flow and inhibition of ADP-induced platelet aggregation with antithrombotic ED50 values of 3.0 and 10 μg/kg/min, respectively. The doses that induced a larger than 3-fold increase in bleeding time were 33 and 100 μg/kg/min for 3 and 13, respectively. Thus, the therapeutic index (TI) was ≥ 10 for both compounds. On the basis of these data, compound 3 was progressed into human clinical trials as candidate drug AZD1283.

Topics: Animals; CHO Cells; Cricetinae; Cricetulus; Dogs; Humans; Niacin; Receptors, Purinergic P2Y12; Sulfonamides; Thrombosis

With the arrival of the potent P2Y12 antagonists, ticagrelor and prasugrel, the need for co-treatment with aspirin in acute coronary syndromes must be re-examined. This study assessed whether high-dose aspirin: a) provides additional anti-platelet efficacy, assessed in vivo and ex vivo, when combined with P2Y12 inhibition; and/or b) has a negative effect on vascular function.. Using an anaesthetized dog model of thrombosis, the effects of aspirin (50mg/kg) in addition to clopidogrel and ticagrelor were evaluated at two levels of P2Y12 inhibition, maximal (≥96%) and sub-maximal (~80%), as assessed by ex vivo ADP-induced whole blood impedence aggregometry.. In the absence of aspirin, maximal and sub-maximal P2Y12 inhibition inhibited arachidonic acid-induced platelet aggregation by approximately 80% and 24%, respectively, without affecting platelet TXA2 formation. During maximal P2Y12 inhibition, aspirin provided less additional inhibition of ex vivo arachidonic acid- and collagen-induced platelet aggregation, as compared with sub-maximal P2Y12 inhibition, without additional anti-thrombotic effect in vivo. Aspirin significantly decreased in vivo PGI2 production (27%) and increased vascular resistance (16%), independently of P2Y12 antagonism.. In the dog, P2Y12 antagonists inhibit TXA2-mediated platelet-aggregation independently of aspirin. Aspirin provides less additional anti-platelet effects during maximal compared with sub-maximal P2Y12 inhibition but increases vascular resistance.

Topics: Adenosine; Animals; Arachidonic Acid; Aspirin; Clopidogrel; Dogs; Dose-Response Relationship, Drug; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor; Ticlopidine; Vascular Resistance

We examined the applicability of contrast-enhanced ultrasound (CEUS) for imaging of murine deep vein thrombosis (DVT) and measured the effects of enoxaparin, ticagrelor and P2Y(12) receptor deficiency in vivo.. Deep vein thrombosis was induced by exposure to ferric chloride or ligation of the infrarenal vena cava of C57BL/6 mice after pretreatment with enoxaparin, ticagrelor or vehicle and in P2Y(12-/-) mice. Initial thrombus growth was visualized by intravital microscopy. Thrombi were weighed and examined by immunohistochemistry. CEUS was performed with a standard ultrasound system (Vivid 7, GE Healthcare) in the open abdominal cavity after injection of stabilized sulphur hexafluoride microbubbles.. Incubation with ferric chloride resulted in non-occluding platelet-containing thrombus growth within 15-25 min. Sham-operated mice, enoxaparin- and ticagrelor-pretreated wild-type and P2Y(12-/-) mice developed only small thrombi. After injection of the contrast agent, growing thrombi were delineated clearly as negative contrast on CEUS. Thrombus size on CEUS after 25 min was significantly smaller in enoxaparin- (0.3 ± 0.1 mm(2)) and ticagrelor-treated (0.5 ± 0.1 mm(2)) wild-type and in P2Y(12-/-) mice (0.4 ± 0.1 mm(2)) as compared with vehicle-treated wild-type mice (2.0 ± 0.3 mm(2)) in the maximal sagittal plane (P < 0.001, n = 5-10). CEUS-derived thrombus size correlated linearly with thrombus weight and also reflected the extent of ligation-induced DVT.. Contrast-enhanced ultrasound allowed the real-time quantification of DVT in living mice. Genetic and pharmacologic antithrombotic interventions were well reflected by CEUS and suggested an important role of the platelet P2Y(12) receptor in early DVT formation.

Topics: Adenosine; Animals; Anticoagulants; Chlorides; Contrast Media; Enoxaparin; Ferric Compounds; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microbubbles; Microscopy; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Signal Transduction; Sulfur Hexafluoride; Thrombosis; Ticagrelor; Ultrasonography; Vena Cava, Inferior; Venous Thrombosis

Topics: Acute Coronary Syndrome; Adenosine; Female; Humans; Male; Middle Aged; Postoperative Complications; Preoperative Care; Purinergic P2Y Receptor Antagonists; Retrospective Studies; Stents; Thrombosis; Ticagrelor

Ticagrelor has been promoted to reduce the rate of definite stent thrombosis compared to clopidogrel from the The Platelet Inhibition and Patient Outcomes (PLATO) trial. However, several issues prevent this statement from being accurate, (1) stent thrombosis was an exploratory endpoint in PLATO--cases were retrospectively and prospectively adjudicated, (2) Sampling/ascertainment bias most likely lead to these conclusions, (3) Stent thromboses were not confirmed by an angiographic core lab (a requirement by the ARC definition for 'definite stent thrombosis'), (4) The integrity of the mortality and MI data from the PLATO trial have recently been challenged. A statement that ticagrelor reduces definite stent thrombosis versus clopidogrel cannot be justified.

Topics: Adenosine; Clopidogrel; Drug-Eluting Stents; Humans; Randomized Controlled Trials as Topic; Thrombosis; Ticagrelor; Ticlopidine; United States; United States Food and Drug Administration

Prasugrel is a third-generation thienopyridine prodrug and ticagrelor is a non-competitive P2Y12 receptor antagonist. In their phase 3 studies, both agents reduced rates of ischemic events relative to treatment with clopidogrel.. The pharmacodynamic profile of anti-platelet effects of prasugrel was compared with that of ticagrelor in rats.. The active metabolite of prasugrel was less potent than ticagrelor and its active metabolite on platelet aggregation in vitro. In contrast, prasugrel was a more potent antiplatelet agent than ticagrelor on ex vivo platelet aggregation: their ED50 values at peak for ADP 20 μmol·L(-1) were 1.9 and 8.0 mg·kg(-1) , respectively. Prasugrel's inhibition of platelet aggregation was maintained for up to 24 h after administration, but ticagrelor's duration of action was substantially shorter. Prasugrel and ticagrelor significantly inhibited thrombus formation with ED50 values of 1.8 and 7.7 mg·kg(-1) , respectively. Both agents also prolonged bleeding times (ED200 values of 3.0 and 13 mg·kg(-1) respectively) suggesting that at equivalent levels of inhibition of platelet aggregation, the agents would show comparable antithrombotic activity with similar bleeding risk. Platelet transfusion significantly increased blood platelet numbers similarly in prasugrel- and ticagrelor-treated rats. In the prasugrel-treated group, platelet transfusion caused significant shortening of bleeding time, while in the ticagrelor-treated group, platelet transfusion showed no influence on bleeding time under the experimental conditions employed.. Prasugrel and ticagrelor showed several differences in their pharmacological profiles and these disparities may reflect their differing reversibility and/or pharmacokinetic profiles.

Topics: Adenosine; Animals; Blood Coagulation Tests; Dose-Response Relationship, Drug; Hemorrhage; Hemostasis; Male; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prodrugs; Purinergic P2Y Receptor Antagonists; Rats; Rats, Sprague-Dawley; Risk; Thiophenes; Thrombosis; Ticagrelor

Little is known about the antiplatelet action of the thienopyridines, clopidogrel and prasugrel, as well as the non-thienopyridine, ticagrelor, in patients suffering from ST-elevation myocardial infarction (STEMI) complicated by cardiogenic shock since systematic comparisons of these antiplatelet agents in this devastating condition are limited so far. This is a report of a patient with STEMI undergoing urgent PCI in cardiogenic shock followed by repeated angioplasty after suffering early stent thrombosis (ST) who showed dual thienopyridine treatment failure of clopidogrel and prasugrel, which was successfully overcome by switching the patient to the non-thienopyridine derivative ticagrelor.

Topics: Adenosine; Aged; Cardiopulmonary Resuscitation; Clopidogrel; Humans; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Shock, Cardiogenic; Stents; Thiophenes; Thrombosis; Ticagrelor; Ticlopidine

Ticagrelor, a cyclopentyltriazolopyrimidine (CPTP), is the representative of a new chemical class of P2Y(12) receptor inhibitors that differ from thienopyridines (ticlopidin, clopidogrel, prasugrel) as ticagrelor is not a prodrug requiring active biotransformation by cytochromes in the liver and thus is characterized by a more rapid, more effective and more consistent platelet inhibition than ticlopidin or clopidogrel. An extensive study program for dose finding and safety for AZD6140 (DISPERSE studies) and a large-scaled phase III trial (PLATO) were undertaken on more than 18,000 patients for validation of efficacy and safety. In the PLATO trial, patients presenting with the broad spectrum of ACS, i.e. unstable angina, non-STEMI or STEMI, were randomized to ticagrelor (Brilique, Brilinta) or clopidogrel within 24 hours after onset of symptoms, regardless whether they were allocated to a planned invasive or conservative treatment. Compared to clopidogrel, ticagrelor reduced rates of the primary endpoint consisting of cardiovascular death, non-fatal MI, or stroke, without an excess of the primary safety endpoint that was PLATO-defined major bleedings. Results from the pre-specified confirmatory subgroup of patients undergoing planned invasive treatment was consistent with PLATO main trial. In addition, the primary endpoint, as well as CV death and all cause death were consistently reduced with ticagrelor in numerous exploratory subgroups including STEMI patients, those planned for non-invasive treatment, patients undergoing CABG, patients with renal failure, and those with diabetes mellitus, although patients were pretreated before coronary angiography and patients with clopidogrel pretreatment were not excluded.. The pharmacological properties and convincing study results of the PLATO trial have stimulated a paradigm change for dual antiplatelet therapy. The new ESC guidelines on the management of ACS without ST segment elevation recommend the use of clopidogrel only when a new antiplatelet drug, e.g. ticagrelor or prasugrel is not available or contraindicated.

Topics: Adenosine; Evidence-Based Medicine; Fibrinolytic Agents; Humans; Purinergic P2Y Receptor Antagonists; Thrombosis; Ticagrelor; Treatment Outcome

Topics: Adenosine; Angina, Unstable; Humans; Myocardial Infarction; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Thrombosis; Ticagrelor

Topics: Acute Coronary Syndrome; Adenosine; Advisory Committees; Aspirin; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Clopidogrel; Drug Approval; Humans; Multicenter Studies as Topic; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Thrombosis; Ticagrelor; Ticlopidine; United States

Topics: Acute Coronary Syndrome; Adenosine; Adult; Atherosclerosis; Humans; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Thrombosis; Ticagrelor

Ticagrelor has been shown to be superior to clopidogrel in patients presenting with acute myocardial infarction who undergo early invasive treatment. We discuss a hitherto unreported use of ticagrelor in the management of a patient resistant to multiple thienopyridines at high risk of stent thrombosis.

Topics: Adenosine; Aged, 80 and over; Cardiac Catheterization; Clopidogrel; Drug-Eluting Stents; Humans; Male; Myocardial Infarction; Purinergic P2Y Receptor Antagonists; Thienopyridines; Thrombosis; Ticagrelor; Ticlopidine; Treatment Outcome

Platelet P2Y₁₂ receptors play an important role in arterial thrombosis by stimulating thrombus growth. Both irreversibly (clopidogrel) and reversibly binding (ticagrelor, AZD6140) P2Y₁₂ antagonists are clinically used for restricted periods, but possible differences in platelet function recovery after drug cessation have not been investigated. We treated WKY rats with a single, high dose of 200 mg/kg clopidogrel or 40 mg/kg ticagrelor. Blood was collected at different time points after treatment. Flow cytometry confirmed full platelet protection against ADP-induced αIIbβ₃ activation shortly after clopidogrel or ticagrelor treatment. At later time points after clopidogrel treatment, a subpopulation of juvenile platelets appeared that was fully responsive to ADP. Addition of ticagrelor to clopidogrel-treated blood reduced αIIbβ₃ activation of the unprotected platelets. In contrast, at later time points after ticagrelor treatment, all platelets gradually lost their protection against ADP activation. Perfusion experiments showed abolishment of thrombus formation shortly after clopidogrel or ticagrelor treatment. Thrombus formation on collagen was determined under high shear flow conditions. At later time points, large thrombi formed in the clopidogrel but not in the ticagrelor group, and unprotected, juvenile platelets preferentially incorporated into the formed thrombi. However, platelets from both groups were still similarly reduced in assays of whole blood aggregation. Conclusively, recovery of rat platelet function after ticagrelor differs mechanistically from that after clopidogrel. This difference is masked by conventional platelet aggregation methods, but is revealed by thrombus formation measurement under flow. Juvenile platelets formed at later time points after clopidogrel treatment promoted thrombus formation.

Topics: Adenosine; Adenosine Diphosphate; Animals; Blood Platelets; Clopidogrel; Cytoprotection; Platelet Activation; Protein Binding; Purinergic P2Y Receptor Antagonists; Rats; Rats, Inbred WKY; Thrombosis; Ticagrelor; Ticlopidine

Our goal was to study the effects of ticagrelor on murine platelet function and thrombosis and characterize the time course of P2Y(12) inhibition required to inhibit neointima formation following vascular injury.. Mice were treated with ticagrelor or vehicle. Platelet aggregation and P-selectin expression were assessed over time, and thrombus formation was assessed in laser-injured cremasteric arterioles of P2Y(12)+/+ and P2Y(12)-/- mice. Neointima formation in FeCl(3)-injured carotid artery was assessed in C57BL/6 mice treated with different regimens of ticagrelor. Ticagrelor inhibited platelet aggregation and P-selectin expression in a dose-dependent, reversible manner. Ticagrelor inhibited thrombus formation to the same extent as seen in P2Y(12)-/- mice. Neointima formation was markedly reduced in mice treated with ticagrelor before and 4 hours after injury (neointima area: control, 39 921±22 749 μm(2), versus ticagrelor, 3705±2600 μm(2); P<0.01), whereas administration of ticagrelor either before injury only or from 4 hours postinjury was ineffective.. Ticagrelor effectively and reversibly inhibits P2Y(12)-mediated platelet function and thrombosis in mice. P2Y(12) inhibition is required both at the time of and after injury to effectively inhibit neointima formation. Additional studies are warranted to evaluate the role of P2Y(12) inhibition in preventing restenosis.

Topics: Adenosine; Animals; Bleeding Time; Blood Coagulation; Blood Platelets; Carotid Artery Injuries; Carotid Artery, Common; Carotid Stenosis; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrinolytic Agents; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; P-Selectin; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor; Tunica Intima

Topics: Adenosine; Animals; Blood Coagulation; Blood Platelets; Carotid Artery Injuries; Carotid Artery, Common; Carotid Stenosis; Cell Proliferation; Coronary Restenosis; Fibrinolytic Agents; Humans; Mice; P-Selectin; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor; Tunica Intima

Platelet activation and thrombus renewal are keys to intraluminal thrombus formation and progression of abdominal aortic aneurysms (AAA). This study explored the ability of AZD6140, a P2Y(12) receptor antagonist, to inhibit platelet activation and prevent aneurysm development in a rat experimental model of AAA.. Aortic aneurysms were induced by implanting a segment of sodium dodecyl sulfate-decellularized guinea pig aorta in rat aortas. One day later, rats were randomized to AZD6140 (10 mg/kg twice daily by mouth) or diluent (n = 23 per group) for either 10 (n = 18) or 42 days (n = 28). Adenosine diphosphate (ADP)-mediated platelet aggregation, aneurysm expansion, intraluminal thrombus formation, inflammatory infiltration, matrix metalloproteinase-9 (MMP-9) expression, and smooth muscle cell colonization were measured.. AZD6140 inhibited ADP-induced platelet aggregation in vivo for 12 hours, justifying twice-daily administration in rats. The spontaneous increase in aortic diameter shown in the aneurysmal model (2.22 +/- 0.56 mm at day 10 vs 5.21 +/- 1.22 mm at day 42) was reduced with AZD6140 (3.61 +/- 1.46 mm at day 42, P < .01). This beneficial effect was associated with a significant reduction of thrombus development, platelet CD41 expression (P < .05), and leukocyte infiltration of the mural thrombus at days 10 and 42 (P < .01). MMP-9 expression correlated with mural thrombus area and was significantly reduced by AZD6140 (P < .05). AZD6140 limited elastic fiber degradation (P < .05) and enhanced progressive colonization of the thrombus by smooth muscle cells at day 42 (P < .01).. These data suggest that inhibition of platelet activation limits intraluminal thrombus biologic activities, thereby impairing aneurysm development.

Topics: Adenosine; Adenosine Diphosphate; Animals; Aorta; Aortic Aneurysm, Abdominal; Blood Platelets; Disease Models, Animal; Disease Progression; Elastic Tissue; Guinea Pigs; Inflammation; Male; Matrix Metalloproteinase 9; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Rats; Rats, Inbred Lew; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor; Time Factors; Transplantation, Heterologous

Ticagrelor is an orally active ADP P2Y12 receptor antagonist in development by AstraZeneca plc for the reduction of recurrent ischemic events in patients with acute coronary syndromes (ACS). Prior to the development of ticagrelor, thienopyridine compounds, such as clopidogrel, were the focus of research into therapies for ACS. Although the thienopyridines are effective platelet aggregation inhibitors, they are prodrugs and, consequently, exert a slow onset of action. In addition, the variability in inter-individual metabolism of thienopyridine prodrugs has been associated with reduced efficacy in some patients. Ticagrelor is not a prodrug and exhibits a more rapid onset of action than the thienopyridine prodrugs. In clinical trials conducted to date, ticagrelor was a potent inhibitor of ADP-induced platelet aggregation and demonstrated effects that were comparable to clopidogrel. In a phase II, short-term trial, the bleeding profile of participants treated with ticagrelor was similar to that obtained with clopidogrel; however, an increased incidence of dyspnea was observed - an effect that has not been reported with the thienopyridines. Considering the occurrence of dyspnea, and the apparent non-superiority of ticagrelor to clopidogrel, it is difficult to justify a clear benefit to the continued development of ticagrelor. Outcomes from an ongoing phase III trial comparing ticagrelor with clopidogrel in 18,000 patients with ACS are likely to impact on the future development of ticagrelor.

Topics: Acute Coronary Syndrome; Adenosine; Administration, Oral; Animals; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Molecular Structure; Platelet Aggregation Inhibitors; Structure-Activity Relationship; Thrombosis; Ticagrelor; Treatment Outcome

Ticagrelor (AZD6140), the first reversibly binding oral P2Y(12) receptor antagonist, blocks adenosine diphosphate (ADP)-induced platelet aggregation via a mode of action distinct from that of thienopyridine antiplatelet agents. The latter must be metabolically activated and binds irreversibly to P2Y(12) for the life of the platelet, precluding restoration of hemostatic function without the generation of new platelets. In in vitro studies comparing binding characteristics of ticagrelor and compound 105, a chemical compound indistinguishable from the active metabolite of prasugrel, ticagrelor exhibited 1) an approximately 100-fold higher affinity for P2Y(12) and rapid achievement of equilibrium (vs no equilibrium reached with compound 105) as assessed by radioligand displacement in a receptor filtration binding assay, 2) 48-fold greater potency in a functional receptor assay using recombinant human P2Y(12), and 3) 63-fold greater potency in inhibiting ADP-induced aggregation in washed human platelets. In rat and dog models of thrombosis/hemostasis, there was greater separation between doses that provided antithrombotic effect and those that increased bleeding for ticagrelor compared with clopidogrel and compound 072, a chemical compound indistinguishable from the prasugrel parent compound. The ratio of dose resulting in 3-fold increase in bleeding time to dose resulting in 50% restoration of blood flow in rats was 9.7 for ticagrelor compared with 2.0 for clopidogrel and 1.4 for compound 072. Similar results were observed in dogs. Our findings suggest that reversibility of P2Y(12) binding with ticagrelor may account for the greater separation between antithrombotic effects and increased bleeding compared with the irreversible binding of clopidogrel and prasugrel.

Topics: Adenosine; Animals; CHO Cells; Clopidogrel; Cricetinae; Cricetulus; Disease Models, Animal; Dogs; Hemostasis; Humans; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Pyridines; Rats; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Thiophenes; Thrombosis; Ticagrelor; Ticlopidine; Transfection

Starting from adenosine triphosphate (ATP), the identification of a novel series of P2Y(12) receptor antagonists and exploitation of their SAR is described. Modifications of the acidic side chain and the purine core and investigation of hydrophobic substituents led to a series of neutral molecules. The leading compound, 17 (AZD6140), is currently in a large phase III clinical trial for the treatment of acute coronary syndromes and prevention of thromboembolic clinical sequelae.

Topics: Adenosine; Adenosine Triphosphate; Administration, Oral; Animals; Humans; Membrane Proteins; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor