prasugrel-hydrochloride and Cardiovascular-Diseases

Antiplatelet medications remain a cornerstone of therapy for atherosclerotic cardiovascular and cerebrovascular diseases. In primary prevention (patients with cardiovascular risk factors but no documented events, symptoms or angiographic disease), there is little evidence of benefit of any antiplatelet therapy, and such therapy carries the risk of excess bleeding. Where there is documented disease (secondary prevention), stable patients benefit from long-term antiplatelet monotherapy, aspirin being first choice in those with coronary heart disease and clopidogrel in those with cerebrovascular disease; moreover, recent evidence shows that low-dose rivaroxaban in combination with aspirin confers added benefit, in patients with stable cardiovascular and peripheral arterial disease. In patients with acute cerebrovascular disease, aspirin combined with clopidogrel reduces subsequent risk, while in acute coronary syndrome, dual antiplatelet therapy comprising aspirin and a P2Y

Topics: Acute Coronary Syndrome; Aspirin; Cardiovascular Diseases; Clopidogrel; Hemorrhage; Humans; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Ticagrelor

Acute coronary syndrome (ACS) is a major cause of morbidity and mortality in the United States with an annual incidence of approximately 1 million. Dual antiplatelet therapy (DAPT), consisting of aspirin and a P2Y12 inhibitor (clopidogrel, ticagrelor, or prasugrel) reduces cardiovascular event rates after ACS.. In 2016, the updated guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) recommended aspirin plus a P2Y12 inhibitor for at least 12 months for patients with ACS. Since these recommendations were published, new randomized clinical trials have studied different regimens and durations of antiplatelet therapy. Recommendations vary according to the risk of bleeding. If bleeding risk is low, prolonged DAPT may be considered, although the optimal duration of prolonged DAPT beyond 1 year is not well established. If bleeding risk is high, shorter duration (ie, 3-6 months) of DAPT may be reasonable. A high risk of bleeding traditionally is defined as a 1-year risk of serious bleeding (either fatal or associated with a ≥3-g/dL drop in hemoglobin) of at least 4% or a risk of an intracranial hemorrhage of at least 1%. Patients at higher risk are 65 years old or older; have low body weight (BMI <18.5), diabetes, or prior bleeding; or take oral anticoagulants. The newest P2Y12 inhibitors, prasugrel and ticagrelor, are more potent, with high on-treatment residual platelet reactivity of about 3% vs 30% to 40% with clopidogrel and act within 30 minutes compared with 2 hours for clopidogrel. Clinicians should avoid prescribing prasugrel to patients with a history of stroke or transient ischemic attack because of an increased risk of cerebrovascular events (6.5% vs 1.2% with clopidogrel, P = .002) and should avoid prescribing it to patients older than 75 years or who weigh less than 60 kg. The ISAR-REACT-5 trial found that prasugrel reduced rates of death, myocardial infarction, or stroke at 1 year compared with ticagrelor among patients with ACS undergoing percutaneous coronary intervention (9.3% vs 6.9%, P = .006) with no significant difference in bleeding. Recent trials suggested that discontinuing aspirin rather than the P2Y12 inhibitor may be associated with better outcomes.. Dual antiplatelet therapy reduces rates of cardiovascular events in patients with acute coronary syndrome. Specific combinations and duration of dual antiplatelet therapy should be based on patient characteristics-risk of bleeding myocardial ischemia.

Topics: Acute Coronary Syndrome; Administration, Oral; Aspirin; Cardiovascular Diseases; Clopidogrel; Drug Therapy, Combination; Humans; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Ticagrelor

Topics: Cardiovascular Diseases; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Secondary Prevention; 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

Topics: Adenosine; Administration, Oral; Cardiovascular Diseases; Humans; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Ticlopidine

The pharmacological and clinical differences of the three recommended oral P2Y

Topics: Adenosine Monophosphate; Administration, Intravenous; Administration, Oral; Blood Platelets; Cardiovascular Diseases; Clinical Decision-Making; Clopidogrel; Drug Substitution; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Ticagrelor; Treatment Outcome

Background As reports on the influence of cigarette smoking, an important cardiovascular risk factor, on platelet ADP -P2Y12 receptor inhibitors lack consistency, we aimed to assess the effectiveness and safety of platelet ADP -P2Y12 receptor inhibitors influenced by smoking status. Methods and Results PubMed, Web of Science, EMBASE , Clinical Trials, and the Cochrane Library were searched from inception until June 2018. Among the 5076 citations retrieved, 22 studies, including 163 011 patients with or without percutaneous coronary intervention, were included for meta-analysis. Compared with nonsmokers within the first year of follow-up, the reductions of stroke and major adverse cardiovascular event rate were 18% ( P=0.008) and 26% ( P=0.02), respectively. A 20% reduction in stroke ( P=0.02) and a 34% reduction in major adverse cardiovascular event ( P=0.0001) rates were observed in smoking patients without percutaneous coronary intervention. No significant difference was observed in clinical outcome rates among prasugrel, ticagrelor, and clopidogrel in different smoking status. No significant difference was found in myocardial infarction and bleeding event incidence between current smokers and nonsmokers. Conclusions We concluded that current smokers had a lower incidence of major adverse cardiovascular events and stroke events than did nonsmokers, particularly in the early period (1 year) and among patients without percutaneous coronary intervention. However, because of the lack of original adjusted data, smoker's paradox still needs to consider the impact of age and other covariates. Thus, a differential risk-benefit evaluation should be considered, according to different smoking status, patient conditions, and therapy time points.

Topics: Acute Coronary Syndrome; Aged; Cardiovascular Diseases; Cigarette Smoking; Clopidogrel; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Stroke; Ticagrelor; Treatment Outcome

Aspirin and P2Y

Topics: Adenosine; Aspirin; Cardiovascular Diseases; Clopidogrel; Drug Administration Schedule; Drug Dosage Calculations; Drug Interactions; Esomeprazole; Gastrointestinal Hemorrhage; Gene Expression; Humans; Hydrogen-Ion Concentration; Peptic Ulcer; Prasugrel Hydrochloride; Proton Pump Inhibitors; Purinergic Antagonists; Receptors, Purinergic P2Y12; Ticagrelor; Ticlopidine

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

Antiplatelet drugs are the cornerstone of therapy in many cardiovascular conditions. With the current success and increased use of transcatheter aortic valve implantation (TAVI), the use of antiplatelet therapy is considered part of the medical therapy for these patients. Clinicians caring for these patients need to have a thorough understanding of the pharmacology, pharmacokinetics, pharmacodynamic, and clinical efficacy and safety of commonly used antiplatelet therapy. While aspirin therapy is widely used, dual antiplatelet therapy with clopidogrel has become part of standard of care. Despite the extensive experience with clopidogrel, there are limitations such as drug interactions, metabolism genetic polymorphisms, and variability in the antiplatelet response. More predictable and more potent antiplatelet agents, prasugrel and ticagrelor, have demonstrated superior reductions in ischemic endpoints as part of dual antiplatelet therapy compared to clopidogrel, but at the cost of more major bleeding in patients with an acute coronary syndrome. Significant research needs to be conducted in the setting of TAVI to help define the optimal antiplatelet regimen.

Topics: Adenosine; Aspirin; Cardiovascular Diseases; Clopidogrel; Humans; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Ticagrelor; Ticlopidine; Transcatheter Aortic Valve Replacement

Type 2 diabetes (T2D) is associated with several abnormalities in haemostasis predisposing to thrombosis. Moreover, T2D was recently connected with a failure in antiplatelet response to clopidogrel, the most commonly used ADP receptor blocker in clinical practice. Clopidogrel high on-treatment platelet reactivity (HTPR) was repeatedly associated with the risk of ischemic adverse events. Patients with T2D show significantly higher residual platelet reactivity on ADP receptor blocker therapy and are more frequently represented in the group of patients with HTPR. This paper reviews the current knowledge about possible interactions between T2D and ADP receptor blocker therapy.

Topics: Adenosine; Adenosine Monophosphate; Blood Platelets; Cardiovascular Diseases; Clopidogrel; Diabetes Mellitus, Type 2; Drug Resistance; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Risk Factors; Ticagrelor; Ticlopidine; Treatment Outcome

Chronic kidney disease has been identified as an independent cardiovascular risk factor. The morbidity and mortality due to cardiovascular disease are higher among chronic kidney disease patients when compared with patients with normal kidney function. Although P2Y12 inhibitors (eg. clopidogrel) are associated with increased survival rates after a myocardial infarction, most of the clinical trials excluded End-Stage Renal Disease (ESRD) patients. Besides, non-responders to P2Y12 inhibitors have been identified as at risk of cardiovascular adverse events and non-responder prevalence is higher among ESRD than in any other population. Recent data questioned the benefits from P2Y12 inhibitors among chronic kidney disease patients. This systematic review aimed to describe pharmacokinetics (PK) and pharmacodynamics (PD) evidence data among 3 widely prescribed P2Y12 inhibitors. Clopidogrel and prasugrel are bioactivated by the cytochromes P450 (CYP) while ticagrelor is already active. PD data used different assays among which the VerifyNow® which showed intravariability before and after dialysis. The potential explanation of modulated PK/PD parameters among ESRD patients will be addressed. Absorption as well as metabolism is diminished in ESRD patients. It could potentially lead to absence of clopidogrel or prasugrel bioactivation or ticagrelor accumulation. Evidence-based recommendation regarding the best option for antiaggregation secondary to percutaneous intervention in this high risk population is still lacking.

Topics: Adenosine; Animals; Cardiovascular Diseases; Clopidogrel; Humans; Kidney Failure, Chronic; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Ticagrelor; Ticlopidine

Topics: Adenosine; Aspirin; Benzimidazoles; beta-Alanine; Cardiovascular Diseases; Clopidogrel; Dabigatran; Drug Interactions; Drug Therapy, Combination; Fibrinolytic Agents; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Proton Pump Inhibitors; Purinergic P2Y Receptor Antagonists; Thiophenes; Ticagrelor; Ticlopidine; Warfarin

Antiplatelet therapy is a cornerstone in the treatment of cardiovascular disease to prevent ischemic events. Various tests have become clinically available to measure platelet function after antiplatelet treatment. A wide interpatient variability in the magnitude of platelet inhibition has been demonstrated in numerous studies, especially in response to clopidogrel. Several reasons including clinical, pharmacological and genetic factors have been identified. High on-clopidogrel platelet reactivity has been linked to adverse clinical outcome, in particular to stent thrombosis after percutaneous coronary interventions. New antiplatelet drugs including prasugrel and ticagrelor have been advocated to overcome the limitations of clopidogrel. Several studies addressed the concept of tailored antiplatelet treatment according to the results of platelet function testing. Within this review, we summarize the current status of personalized antiplatelet therapy for cardiovascular disease.

Topics: Adenosine; Cardiovascular Diseases; Clopidogrel; Humans; Piperazines; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Precision Medicine; Thiophenes; Ticagrelor; Ticlopidine; Treatment Outcome

Topics: Adenosine; Cardiovascular Diseases; Clopidogrel; Coronary Artery Disease; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Thiophenes; Ticagrelor; Ticlopidine; Treatment Outcome

For several years, clopidogrel plus aspirin has been the dual antiplatelet therapy (DAPT) of choice for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) with stent implantation. More recently, prasugrel and ticagrelor have demonstrated greater efficacy than clopidogrel. In TRITON-TIMI 38, the risk of TIMI major bleeding unrelated to coronary artery bypass graft (CABG) surgery was similar for prasugrel and clopidogrel after excluding subgroups with increased bleeding risk (previous stroke or transient ischemic event; age ≥75 years; weight <60 kg). In the PLATO trial, rates of TIMI major bleeding were similar for ticagrelor and clopidogrel, but ticagrelor was associated with a significantly higher rate of non-CABG-related TIMI major bleeding. Current evidence suggests that prasugrel or ticagrelor plus aspirin should be the DAPT of choice in patients with ACS undergoing PCI unless they are at particularly high risk of bleeding. No studies have yet compared prasugrel and ticagrelor in ACS patients, however prasugrel and ticagrelor have different side effect profiles, and the choice of agent should be made either as a default choice and/or on an individual patient basis. Ongoing trials in ACS patients will increase the evidence base for new P2Y(12) receptor inhibitors and help to establish the most effective DAPT regimens.

Topics: Adenosine; Cardiovascular Diseases; Clopidogrel; Humans; Percutaneous Coronary Intervention; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Stents; Thiophenes; Ticagrelor; Ticlopidine; Treatment Outcome

Platelet adhesion, activation and aggregation play a pivotal role in atherothrombosis. Intracoronary atherothrombosis is the most common cause of the development of acute coronary syndrome (ACS), and plays a central role in complications occurring around percutaneous coronary intervention (PCI) including recurrent ACS, procedure-related myocardial infarction or stent thrombosis. Inhibition of platelet aggregation by medical treatment impairs formation and progression of thrombotic processes and is therefore of great importance in the prevention of complications after an ACS or around PCI. An essential part in the platelet activation process is the interaction of adenosine diphosphate (ADP) with the platelet P2Y12 receptor. The P2Y12 receptor is the predominant receptor involved in the ADP-stimulated activation of the glycoprotein IIb/IIIa receptor. Activation of the glycoprotein IIb/IIIa receptor results in enhanced platelet degranulation and thromboxane production, and prolonged platelet aggregation. The objectives of this review are to discuss the pharmacological limitations of the P2Y12 inhibitor clopidogrel, and describe the novel alternative P2Y12 inhibitors prasugrel and ticagrelor and the clinical implications of the introduction of these new medicines.

Topics: Adenosine; Cardiovascular Diseases; Clinical Trials as Topic; Clopidogrel; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thiophenes; Ticagrelor; Ticlopidine

The convention of loading with clopidogrel 300 mg before coronary intervention may be due for change, but to what? Newer antiplatelet agents may offer better outcomes, at some financial cost. Disappointingly for decision-making clinicians, head-to-head comparisons for the newer alternatives are not available. We systematically review and compare the three alternative strategies: clopidogrel 600 mg, prasugrel and ticagrelor. A total of 14 studies have compared these strategies with the long-standing convention of 300 mg. Throughout this analysis, we consistently report incremental costs and consequences using clopidogrel 300 mg as the reference strategy. Risk ratios for major adverse cardiovascular events at 30 days were 0.74 (95% confidence interval 0.66-0.82, p=0.002) for clopidogrel 600 mg, 0.78 (0.69-0.89; p<0.001) for prasugrel and 0.88 (0.77-1.00; p=0.045) for ticagrelor. All-cause mortality risk ratios were 0.87 (0.74-1.03) with clopidogrel 600 mg, 0.95 (0.78-1.16) with prasugrel and 0.78 (0.69-0.89) with ticagrelor. TIMI major bleeding has risk ratio 0.92 (0.74-1.16; p=0.85) with clopidogrel 600 mg, 1.32 (1.03-1.16; p=0.03) with prasugrel and 1.25 (1.03-1.53; p=0.03) with ticagrelor. Incremental cost for the first year was £0.32 (US$0.50, €0.40) with clopidogrel 600 mg, £608 (US$977, €709) with prasugrel and £665 (US$1068, €775) with ticagrelor. All three strategies have shown a similar reduction in MACE at 30 days by comparison to clopidogrel 300 mg. All three strategies offer progressive benefit, most marked with Ticagrelor. Whether this is worth both the risk of non-compliance with twice-a-day dosing in real-life patients lacking the same motivation as their trial-volunteer counterparts, and the 2000-fold difference in incremental cost, is the remaining matter for debate.

Topics: Adenosine; Animals; Cardiovascular Diseases; Clopidogrel; Hemorrhage; Humans; Piperazines; Prasugrel Hydrochloride; Thiophenes; Ticagrelor; Ticlopidine

Over the last two decades or more, anti-platelet therapy has become established as a cornerstone in the treatment of patients with ischaemic cardiovascular disease, since such drugs effectively reduce arterial thrombotic events. The original agent used in this context was aspirin (acetylsalicylic acid) but, with the advent of adenosine diphosphate (ADP) receptor antagonists, the use of dual anti-platelet therapy has resulted in further improvement in cardiovascular outcomes when compared with aspirin alone. The first group of platelet ADP receptor antagonists to be developed was the thienopyridine class, which comprise inactive pro-drugs that require in vivo metabolism to their active metabolites before exerting their inhibitory effect on the P2Y(12) receptor. Clopidogrel has been the principal ADP receptor antagonist in use over the past decade, but is limited by variability in its in vivo inhibition of platelet aggregation (IPA). The pharmacokinetics of clopidogrel are unpredictable due to their vulnerability to multiple independent factors including genetic polymorphisms. Expression of the 3435T/T genetic variant encoding the MDR1 gene for the P-glycoprotein efflux transporter results in a significantly reduced maximum drug concentration and area under the plasma concentration-time curve as intestinal absorption of clopidogrel is reduced; and the expression of the mutant *2 allele of CYP2C19 results in similar pharmacokinetic effects as the two cytochrome P450 (CYP)-mediated steps required for the production of the active metabolite of clopidogrel are impaired. These variable pharmacokinetics lead to erratic pharmacodynamics and cannot reliably be overcome with increased dosing. Both prasugrel, a third-generation thienopyridine, and ticagrelor, a cyto-pentyl-triazolo-pyrimidine, have more predictable pharmacokinetics and enhanced pharmacodynamics than clopidogrel. Neither appears to be affected by the same genetic polymorphisms as clopidogrel; prasugrel requires only a single CYP-mediated step to produce its active metabolite and ticagrelor is not a pro-drug. Enhanced IPA by both prasugrel and ticagrelor is achieved at the expense of increased major bleeding, although this is partially mitigated in the case of ticagrelor due to its reversible IPA. However, the reversible binding of ticagrelor to the P2Y(12) receptor requires a twice-daily dosing regimen. Due to limited data from clinical studies, the use of prasugrel is currently restricted to individu

Topics: Adenosine; Cardiovascular Diseases; Clopidogrel; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Thiophenes; Ticagrelor; Ticlopidine

Since novel antiplatelet treatments (prasugrel, ticagrelor, high-dose clopidogrel) have been predominantly tested against standard-dose clopidogrel, data on direct comparisons between these therapies are scarce. We therefore indirectly compared their efficacy and safety in patients undergoing percutaneous coronary intervention. Electronic databases were searched systematically to identify head-to-head randomised controlled trials (RCTs). Network meta-analysis was performed using generalised linear mixed models with adjustment for length of follow-up. Findings were corroborated by mixed treatment comparison through Bayesian methods. Fourteen RCTs were identified and included in the analysis (high- vs. standard-dose clopidogrel: 9 trials, prasugrel vs. high-dose clopidogrel: 2 trials, prasugrel vs. standard-dose clopidogrel: 2 trials, ticagrelor vs. standard-dose clopidogrel: 1 trial). No significant differences were found for efficacy outcomes except for stent thrombosis favouring prasugrel (vs. ticagrelor: odds ratio [OR] 0.63, 95% confidence interval [CI]: 0.42, 0.94; vs. high-dose clopidogrel: OR 0.70, 95%CI: 0.48, 1.01). Prasugrel exhibited a similar bleeding risk as high-dose clopidogrel, but more major (OR 1.43, 95%CI 1.07, 1.90) and major or minor bleeding (OR 1.36, 95%CI 1.09, 1.69) compared to ticagrelor. Ticagrelor was also associated with less major or minor bleeding compared to high-dose clopidogrel (OR 0.81, 95%CI 0.69, 0.96). No differences were seen for non CABG-related major bleeding between the three strategies. Results were corroborated in a subgroup analysis comprising only patients with acute coronary syndromes. In the absence of head-to-head clinical trials, network meta-analysis suggests potentially relevant differences in efficacy and bleeding risk among novel antiplatelet treatments and may thereby advance understanding of their differential therapeutic properties.

Topics: Acute Coronary Syndrome; Adenosine; Angioplasty; Cardiovascular Diseases; Clopidogrel; Hemorrhage; Humans; Odds Ratio; Percutaneous Coronary Intervention; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Randomized Controlled Trials as Topic; Risk; Stents; Thiophenes; Ticagrelor; Ticlopidine; Treatment Outcome

Although there are many new and effective anti-P2Y(12) drugs available, clopidogrel in its original or generic forms will probably remain the most widely used and cheaper option. As clopidogrel is a pro-drug, there is marked heterogeneity in drug responsiveness between individuals and lack of responsiveness is associated with poorer clinical outcomes. Various platelet function and genetic tests are now available for potentially measuring whether clopidogrel effectively inhibits platelet function. Monitoring of P2Y(12) inhibition and/or identification of loss of function cytochrome P-450 genotypes could, therefore, offer the potential of tailoring therapy by identifying poor responders to clopidogrel and optimizing the levels of platelet inhibition using, for example, alternative drugs such as prasugrel or ticagrelor. The question remains whether any of these tests have prognostic utility with a defined therapeutic window to reliably identify hypo or hyper-responsive patients who may have an increased risk of thrombosis or bleeding, respectively? Once such patients are identified, can the tests then be subsequently used to demonstrate a change or improvement in platelet reactivity by using alternative therapies and equate this with improved clinical outcome? In this review, we describe an overview of the current platelet and genetic tests available and discuss whether these tests will ever become used routinely.

Topics: Adenosine; Blood Platelets; Cardiovascular Diseases; Clopidogrel; Cytochrome P-450 Enzyme System; Humans; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Precision Medicine; Prodrugs; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thiophenes; Ticagrelor; Ticlopidine

Despite improved clinical outcomes from dual anti-platelet therapy with aspirin plus the CYP12 ADP receptor antagonist clopidogrel in patients undergoing coronary revascularisation, ex-vivo platelet function testing consistently reveals a proportion of patients with apparent resistance or non-response to clopidogrel loading and maintenance therapy who are at increased risk of coronary thrombosis. Treatment regimens using the newer CYP12 antagonists prasugrel and ticagrelor demonstrate improved ex-vivo platelet inhibition and superior clinical efficacy in large-scale clinical trials-even in patients demonstrating clopidogrel resistance. However, improved efficacy comes at the cost of an increased overall risk of bleeding for both drugs. Further analysis of the outcomes from large scale clinical studies suggests that individual patient sub-groups differ both in their liklehood of bleeding with newer anti-platelet agents and with regard to efficacy outcomes. Therefore when deciding anti-platelet regimens in suspected acute coronary syndrome, particular consideration must be given to patient's risk of thrombosis (STEMI, previous stent thrombosis), the procedure (complex PCI, thrombus in-situ, strategy of pre-treatment), and factors affecting safety (patient age, patient weight, previous stroke, liklehood of surgical revascularisation). Placing the focus on individualised patient risk-benefit assessment with appropriate use of platelet function testing when indicated, in combination with the ongoing assessment of prasugrel and ticagrelor in larger numbers of patients should be the key strategies governing use of dual anti-platelet therapy.

Topics: Adenosine; Animals; Blood Platelets; Cardiovascular Diseases; Clopidogrel; Drug Design; Drug Resistance; Drug Therapy, Combination; Evidence-Based Medicine; Hemorrhage; Humans; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Predictive Value of Tests; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Risk Assessment; Risk Factors; Thiophenes; Ticagrelor; Ticlopidine

Diabetics have a prothrombotic state that includes increased platelet reactivity. This contributes to the less favorable clinical outcomes observed in diabetics experiencing acute coronary syndromes as well as stable coronary artery disease. Many diabetics are relatively resistant to or have insufficient response to several antithrombotic agents. In the setting of percutaneous coronary intervention, hyporesponsiveness to clopidogrel is particularly common among diabetics. Several strategies have been examined to further enhance the benefits of oral antiplatelet therapy in diabetics. These include increasing the dose of clopidogrel, triple antiplatelet therapy with cilostazol, and new agents such as prasugrel. The large TRITON TIMI 38 randomized trial compared clopidogrel to prasugrel in the setting of percutaneous coronary intervention for acute coronary syndromes. The diabetic subgroup (n = 3146) experienced considerable incremental benefit with a 4.8% reduction in cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke at 15-month follow-up with prasugrel treatment. Among diabetics on insulin this combined endpoint was reduced by 7.9% at 15 months. Major bleeding was not increased in the diabetic subgroup. This confirms the general hypothesis that more potent oral antiplatelet therapy can partially overcome the prothrombotic milieu and safely improve important clinical outcomes in diabetics.

Topics: Administration, Oral; Angioplasty, Balloon, Coronary; Cardiovascular Diseases; Coronary Artery Disease; Diabetes Mellitus; Drug Resistance; Drug Therapy, Combination; Humans; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Stroke; Thiophenes; Thrombosis; Time Factors; Treatment Outcome

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aryl Hydrocarbon Hydroxylases; Aspirin; Cardiovascular Diseases; Clopidogrel; Cytochrome P-450 CYP2C19; Drug Interactions; Drug Therapy, Combination; Gastrointestinal Hemorrhage; Histamine H2 Antagonists; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Proton Pump Inhibitors; Purinergic P2Y Receptor Antagonists; Risk Factors; Thienopyridines; Thiophenes; Ticlopidine

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aryl Hydrocarbon Hydroxylases; Aspirin; Cardiovascular Diseases; Clopidogrel; Cytochrome P-450 CYP2C19; Drug Interactions; Drug Therapy, Combination; Gastrointestinal Hemorrhage; Histamine H2 Antagonists; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Proton Pump Inhibitors; Purinergic P2Y Receptor Antagonists; Risk Factors; Thienopyridines; Thiophenes; Ticlopidine

To review the literature describing the pharmacology, pharmacokinetic properties, efficacy, and adverse effects of prasugrel, a new thienopyridine.. A literature search was conducted (1966-November 2008) of the MEDLINE, Current Contents, EMBASE, and International Pharmaceutical Abstract databases using the key words prasugrel, CS-747, LY640315, and P2Y(12). Bibliographies of identified literature were also reviewed for additional references.. All reports published in English that evaluated prasugrel (or its chemical synonyms) were reviewed. Abstracts without subsequently published reports were excluded.. Given the high rate of recurrent coronary events despite current antiplatelet therapies, agents with potentially greater efficacy are under investigation. Prasugrel is a novel thienopyridine prodrug that is rapidly metabolized to its active platelet-inhibitory metabolite (R-138727) and exerts antiplatelet activity through antagonism of P2Y(12) receptors. Prasugrel is very similar in structure and mechanism of action to clopidogrel, as they both possess a methoxycarbonyl group that provides increased pharmacologic activity and an improved hematologic safety profile when compared with ticlopidine. In addition, when compared with clopidogrel, prasugrel demonstrates greater potency and less interpatient variability in the inhibition of platelet aggregation, less in vitro hyporesponsiveness, and, in patients with acute coronary syndromes, a reduced rate of ischemic events. However, this reduction in ischemic events was accompanied by an increased risk of major and fatal bleeding.. Prasugrel appears to be a promising antiplatelet agent, with emerging clinical data in direct comparison with clopidogrel supporting its role in reducing recurrent ischemic events. Further studies are needed to evaluate the safety and efficacy of prasugrel across various patient populations and clinical scenarios.

Topics: Animals; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Thiophenes

The priority task to develop better and safer antiplatelet agents is difficult to overestimate. In fact, oral antiplatelet agents, such as aspirin in ISIS-2 study, and clopidogrel in COMMIT mega trial in moderate doses are among the very few classes of drugs, which lead to the absolute mortality reduction benefit in patients after acute vascular thrombotic events. Prasugrel is an experimental thienopyridine, and irreversible antagonist of ADP P2Y(12) receptor leading to inhibition of platelet activation and aggregation. The recent TRITON trial, assessing head-to-head prasugrel versus standard of care clopidogrel, both on top of aspirin, reveals numerous controversies with regard to the trial design, definition of events, interpretation of the results, and suitability of the high maintenance prasugrel dose for chronic preventive human use. We critically review various aspects of prasugrel development, focusing on the discrepancies between claims and achievements. We conclude that the benefits of prasugrel are overestimated, and the risks, especially during chronic use are underestimated. Very careful maintenance-dose selection with the main focus on long-term safety profile for the new agents will become a key to success for the future oral antiplatelet drug development.

Topics: Administration, Oral; Angioplasty, Balloon, Coronary; Animals; Aspirin; Blood Platelets; Cardiovascular Diseases; Clinical Trials as Topic; Clopidogrel; Drug Administration Schedule; Drug Discovery; Drug Resistance; Hemorrhage; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Research Design; Risk Assessment; Stents; Thiophenes; Ticlopidine; Treatment Outcome

The role of antiplatelet therapy in the management of coronary artery disease and its sequalae is of great significance. Acetil Salycilic Acid (ASA) has continued to dominate the field as a potent antiplatelet agent, due to its ease of use and cost effectiveness. In addition to this, clopidogrel has also been widely used with better long term administration results in patients with atherosclerotic disease. However, interpatient variability and resistance to clopidogrel has opened the doors for further investigative research to find another agent which potentially meets the pharmacokinetic demands whilst having a satisfactory safety profile. Prasugrel and other novel nonthienopyridine derivatives are currently under investigation, with previous trials showing very reassuring outcomes. Patented inventions along with large trials have shown that prasugrel significantly reduces ischemic end points, ultimately resulting in a decrease in Myocardial infarctions, thromboocculusive episodes and death. Further studies are required to support these findings before we are aware of all clinical effects of Prasugrel.

Topics: Adenosine; Adenosine Monophosphate; Cardiovascular Diseases; Clinical Trials as Topic; Clopidogrel; Humans; Imines; Lactones; Patents as Topic; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Pyridines; Receptor, PAR-1; Receptors, Purinergic P2Y12; Receptors, Thrombin; Thiophenes; Ticagrelor; Ticlopidine

This article reviews: 1) some of the results of drug eluting stents (SYNTAX and FAME); 2) the questionnable benefit of physical training in heart failure patients (HF-ACTION); 3) the benefit on cardiac remodelling of cardiac resynchronisation in heart failure patients (REVERSE study) and 4) the role of rate over rhythm control in patients with atrial fibrillation and heart failure (AF-CHF study); this article also reports the encouraging evolution of new technology allowing percutaneous implantation of stents-valves. Finally, this article address the screening of athletes for cardiac diseases.

Topics: Cardiac Pacing, Artificial; Cardiovascular Diseases; Death, Sudden; Drug-Eluting Stents; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Sports; Thiophenes

Platelets are major players in arterial thrombosis, and antiplatelet therapy has a clear clinical benefit in the treatment and prevention of cardiovascular events. In particular, aspirin and clopidogrel have become cornerstones in the treatment of patients with atherothrombosis. However, despite the proven efficacy of antiplatelet drugs, cardiovascular events remain an important cause of morbidity and mortality in these patients. Furthermore, a considerable variability in platelet reactivity during treatment with established oral antiplatelet therapy has prompted the search for novel drugs against platelet-dependent thrombosis. Possible benefits of upcoming drugs include a more efficient platelet inhibition and a reversible effect on platelet function. Aspirin, clopidogrel, prasugrel, ticagrelor, terutroban, E5555, SCH 530348 and cilostazol are discussed. This review highlights the rationale for important oral antiplatelet drugs in development and provides clinical perspectives on their pharmacological advantages and challenges.

Topics: Adenosine; Administration, Oral; Cardiovascular Diseases; Cilostazol; Coronary Artery Disease; Coronary Thrombosis; Drug Resistance; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Tetrazoles; Thiophenes; Thromboxane A2; Ticagrelor

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

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

Aspirin is the foundation antiplatelet therapy for patients at risk of cardiovascular events. The thienopyridine, clopidogrel, is modestly more effective than aspirin and in patients with stroke seems to be as effective as the combination of aspirin and dipyridamole. The addition of clopidogrel to aspirin further reduces the risk of cardiovascular events in patients with acute coronary syndromes and those who undergo percutaneous coronary intervention, but uncertainty remains about whether this combination has incremental efficacy over clopidogrel monotherapy in patients with stroke or peripheral arterial disease. Clopidogrel has pharmacological limitations that have prompted the search for more effective ADP-receptor antagonists. Promising results have been achieved with the thienopyridine, prasugrel, which has been compared with clopidogrel in patients treated with aspirin. The nonthienopyridine P2Y(12) inhibitors AZD6140 and cangrelor are presently being evaluated in phase III, randomized, controlled trials.

Topics: Adenosine; Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Aspirin; Blood Platelets; Cardiovascular Diseases; Clopidogrel; Drug Therapy, Combination; History, 20th Century; History, 21st Century; Humans; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Stents; Thiophenes; Ticagrelor; Ticlopidine; Treatment Outcome

Platelets play an important role in atherothrombotic disease, as well as in the pathogenesis of atherosclerosis and in complications. Antiplatelet therapy with clopidogrel represents at present an important treatment of coronary artery disease (CAD), especially in and after acute coronary syndromes (ACS), and after coronary interventions when stents are used. Clopidogrel is a potent and specific inhibitor of platelet ADP receptor (P2Y(12) receptor) with high antithrombotic activity. Emerging data suggest that a significant percentage of individuals treated with clopidogrel do not receive the expected therapeutic benefit because of a decreased responsiveness of their platelets, which is caused by several extrinsic and/or intrinsic mechanisms. As long as clopidogrel is the "gold standard" in combination with aspirin in the treatment of patients undergoing percutaneous coronary intervention and stent implantation, the overall challenge is to develop a fast "point-of-care" assay to detect clopidogrel resistance early and to enable alternative antithrombotic strategies in non-responders or low-responders. This test should be easily performed (bedside) and reproducible, with a standardized definition of response, which is known to correlate with clinical outcomes. Unfortunately, such a test does not exist at present. As an alternative, new ADP receptor antagonists with better bioavailability and improved pharmacokinetics, e.g. intestinal reabsorption as an active drug or 1:1 conversion into an active metabolite thus reducing individual variations, are in development and have already found their way into clinical use in phase-3 trials. Prasugrel is one of the incoming new drugs with high expectations, but other agents might follow in the near future.

Topics: Blood Platelets; Cardiovascular Diseases; Clopidogrel; Drug Design; Drug Resistance; Drugs, Investigational; Humans; Membrane Proteins; Piperazines; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Pyridines; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Thiophenes; Ticlopidine

Background The ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) was a large, pragmatic, randomized controlled trial that found no difference between high- versus low-dose aspirin for secondary prevention of atherosclerotic cardiovascular disease. Whether concomitant P2Y12 inhibitor therapy modifies the effect of aspirin dose on clinical events remains unclear. Methods and Results Participants in ADAPTABLE were stratified according to baseline use of clopidogrel or prasugrel (P2Y12 group). The primary effectiveness end point was a composite of death, myocardial infarction, or stroke; and the primary safety end point was major bleeding requiring blood transfusions. We used multivariable Cox regression to compare the relative effectiveness and safety of aspirin dose within P2Y12 and non-P2Y12 groups. Of 13 815 (91.6%) participants with available data, 3051 (22.1%) were receiving clopidogrel (2849 [93.4%]) or prasugrel (203 [6.7%]) at baseline. P2Y12 inhibitor use was associated with higher risk of the primary effectiveness end point (10.86% versus 6.31%; adjusted hazard ratio [HR], 1.40 [95% CI, 1.22-1.62]) but was not associated with bleeding (0.95% versus 0.53%; adjusted HR, 1.42 [95% CI, 0.91-2.22]). We found no interaction in the relative effectiveness and safety of high- versus low-dose aspirin by P2Y12 inhibitor use. Overall, dose switching or discontinuation was more common in the high-dose compared with low-dose aspirin group, but the pattern was not modified by P2Y12 inhibitor use. Conclusions In this prespecified analysis of ADAPTABLE, we found that the relative effectiveness and safety of high- versus low-dose aspirin was not modified by baseline P2Y12 inhibitor use. Registration https://www.clinical.trials.gov. Unique identifier: NCT02697916.

Topics: Acute Coronary Syndrome; Aspirin; Atherosclerosis; Cardiovascular Diseases; Clopidogrel; Hemorrhage; Humans; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Secondary Prevention; Ticlopidine

The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated.. In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel.. At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group.. Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).

Topics: Acute Coronary Syndrome; Aged; Angina, Unstable; Aspirin; Cardiovascular Diseases; Clopidogrel; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Stroke; Thiophenes; Ticlopidine

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Cardiovascular Diseases; Clopidogrel; Double-Blind Method; Hemorrhage; Humans; Ischemic Attack, Transient; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prospective Studies; Secondary Prevention; Stents; Stroke; Thiophenes; Ticlopidine; Treatment Outcome

Despite the current standard antiplatelet regimen of aspirin and clopidogrel (with or without glycoprotein IIb/IIIa inhibitors) in percutaneous coronary intervention patients, periprocedural and postprocedural ischemic events continue to occur. Prasugrel (CS-747, LY640315), a novel potent thienopyridine P2Y(12) receptor antagonist, has the potential to achieve higher levels of inhibition of ADP-induced platelet aggregation than currently approved doses of clopidogrel.. Joint Utilization of Medications to Block Platelets Optimally-Thrombolysis In Myocardial Infarction 26 (JUMBO-TIMI 26) was a phase 2, randomized, dose-ranging, double-blind safety trial of prasugrel versus clopidogrel in 904 patients undergoing elective or urgent percutaneous coronary intervention. Patients were randomized to either standard dosing with clopidogrel or 1 of 3 prasugrel regimens. Subjects were monitored for 30 days for bleeding and clinical events. The primary end point of the trial was clinically significant (TIMI major plus minor) non-CABG-related bleeding events in prasugrel- versus clopidogrel-treated patients. Hemorrhagic complications were infrequent, with no significant difference between patients treated with prasugrel or clopidogrel in the rate of significant bleeding (1.7% versus 1.2%; hazard ratio, 1.42; 95% CI, 0.40, 5.08). In prasugrel-treated patients, there were numerically lower incidences of the primary efficacy composite end point (30-day major adverse cardiac events) and of the secondary end points myocardial infarction, recurrent ischemia, and clinical target vessel thrombosis.. In this phase 2 study, which was designed to assess safety when administered at the time of percutaneous coronary intervention, prasugrel and clopidogrel both resulted in low rates of bleeding. The results of this trial serve as a foundation for the large phase 3 clinical trial designed to assess both efficacy and safety.

Topics: Adolescent; Adult; Aged; Angioplasty, Balloon, Coronary; Cardiovascular Diseases; Clopidogrel; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hemorrhage; Humans; Incidence; Male; Membrane Proteins; Middle Aged; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Pyridines; Receptors, Purinergic P2Y12; Thiophenes; Ticlopidine

Several Caucasian cohort studies have associated at least one loss-of-function CYP2C19 on Clopidogrel (LoF-Clopidogrel) with major adverse cardiovascular events (MACE), and only a couple have used Clinical Pharmacogenetics Implementation Consortium (CPIC. A retrospective genotype study was performed on 238 percutaneous coronary intervention subjects, originally planned for escalation of antiplatelets using platelet reactivity testing.. There was no difference in MACE between the switched and unswitched groups; however, 'all bleeds' and 'clinically significant bleeds' (CSB) were statistically higher in the patients who were switched to prasugrel. The subgroup of patients who remained on clopidogrel (n = 199) were analysed using phenotype categories and MACE. Eleven percent (11.4%) of CYP2C19 poor metabolizers (PM) suffered MACE, compared with 1.3% of extensive metabolizers (EM). LoF-Clopidogrel patients are significantly more likely to experience MACE compared with non-LoF subjects (8.0% vs 5.4%, P: .041).. In our multivariate analysis, LoF-Clopidogrel, malay ethnicity, diabetics and use of proton pump inhibitors were independent predictors of MACE. There were numerically more bleeds in LoF subjects who were on prasugrel compared with Clopidogrel (23.5% vs 11%, P = .082). Our data corroborate with current findings on platelet reactivity testing, suggesting that the assay would not be sensitive enough to pick up sufficient 'at-risk' subjects as compared to the use of CYP2C19 genotyping.

Topics: Acute Coronary Syndrome; Aged; Asian People; Cardiovascular Diseases; Clopidogrel; Cytochrome P-450 CYP2C19; Female; Genotype; Hemorrhage; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Pharmacogenetics; Phenotype; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Retrospective Studies

To investigate the long-term clinical benefit of dual antiplatelet therapy with potent P2Y12 inhibitors compared to clopidogrel in patients with acute coronary syndrome (ACS).. In this prospective multicenter observational study, we enrolled 708 patients with ACS treated with clopidogrel (n = 137), ticagrelor (n = 260) or prasugrel (n = 311). Major adverse cardiac events (MACE; over 1 year) and long-term mortality (median: 5.6 years; interquartile range [IQR] 4.9-6.5 years) were assessed. Multiple electrode aggregometry (MEA) was used to measure adenosine diphosphate (ADP)- and arachidonic acid (AA)-induced platelet aggregation.. Type of P2Y12 inhibitor emerged as an independent predictor of long-term mortality and MACE: patients treated with potent platelet inhibitors prasugrel or ticagrelor were at lower risk for long-term mortality (adjusted hazard ratio [HR] = 0.44; 95% CI: 0.22-0.92; P = .028) or MACE (adjusted HR = 0.38; 95% CI: 0.20-0.73; P = .004) than those treated with clopidogrel independent from clinical risk factors. In contrast, the efficacy of clopidogrel decreased with increasing severity of ACS: platelet aggregation was 37% higher in patients with ST segment elevation myocardial infarction (STEMI) and 25% higher in patients with non-ST elevation myocardial infarction (non-STEMI) compared to patients with unstable angina (P = .039). Patients with diabetes achieved less potent ADP- and AA-induced platelet inhibition under clopidogrel, compared to patients without diabetes (P = .045; P = .030, respectively).. In the setting of ACS, treatment with ticagrelor or prasugrel reduced long-term mortality and 1-year MACE as compared to clopidogrel.

Topics: Acute Coronary Syndrome; Adenosine Diphosphate; Aged; Arachidonic Acid; Aspirin; Cardiovascular Diseases; Clopidogrel; Dual Anti-Platelet Therapy; Female; Humans; Male; Middle Aged; Mortality; Myocardial Infarction; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Prognosis; Proportional Hazards Models; Prospective Studies; Secondary Prevention; Stroke; Survival Rate; Ticagrelor

Background Peripheral artery disease (PAD) is a known risk factor for adverse outcomes in patients undergoing percutaneous coronary intervention. However, in some studies PAD is not an independent risk factor. We sought to examine the independent impact of PAD on a large prospective percutaneous coronary intervention registry. Methods and Results From our single-center prospective percutaneous coronary intervention registry, we have retrospectively analyzed 25 690 patients (years 2004-2018). We examined the influence of PAD on short- and long-term outcomes using both regression and propensity-matched analyses. Patients with documented PAD (n=1610, 6.3% of total) were older (66.7±10.8 versus 65.4±12.1,

Topics: Aged; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus; Female; Humans; Hypertension; Male; Middle Aged; Percutaneous Coronary Intervention; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prospective Studies; Purinergic P2Y Receptor Antagonists; Registries; Renal Insufficiency; Retrospective Studies; Risk Factors; Ticagrelor; Treatment Outcome

Trends and clinical factors associated with prescribing choices for oral P2Y12 inhibitors (P2Y12-I) remain unknown for patients on chronic dialysis, i.e., with end-stage renal disease (ESRD).. From 2011-2014 U.S. Renal Data System registry, we identified 36,542 ESRD patients who received new prescriptions for P2Y12-I (median age 64.0 years and 54% males). Of the cohort, 93% were receiving hemodialysis and 7% on peritoneal dialysis. We analyzed trends and investigated clinical factors associated with specific P2Y12-I prescribed.. Clopidogrel was prescribed for 95%, prasugrel for 3%, and ticagrelor for 2%. Clopidogrel was favored for those ≥75 years (18% of cohort). Compared to Caucasians, African Americans (36% of cohort) and Hispanics (19% of cohort) were less likely to receive prasugrel and ticagrelor (P<0.05). Patients receiving hemodialysis versus peritoneal dialysis were less likely to receive prasugrel over clopidogrel, adjusted odds ratio (aOR) 0.67 (0.55-0.82). Each additional year of dialysis decreased the odds of receiving prasugrel over clopidogrel, aOR 0.91 (0.85-0.98). History of atrial fibrillation reduced the odds of receiving ticagrelor or prasugrel over clopidogrel, aOR 0.69 (0.54-0.89) and 0.73 (0.60-0.89), respectively. Concomitant oral anticoagulant use was not associated with choice of P2Y12-I. Occurrence of non-ST segment elevation myocardial infarction or percutaneous coronary intervention within the 6-month period prior to the index date favored ticagrelor over prasugrel, aOR 1.31 (1.06-1.62) and 1.29 (1.01-1.66), respectively. However, prescribing trends favoring ticagrelor over prasugrel were not observed for deployment of drug-eluting, or multiple coronary stents.. Between 2011 and 2014, clopidogrel remained the most common P2Y12-I whereas ticagrelor and prasugrel remained underutilized in ESRD patients. Prescribing practices for these drugs were based upon clinically approved indication for their use in the general population as well as perceived complexity of an ESRD patient including demographics, dialysis-related factors and comorbidities. Comparative effectiveness studies involving ESRD patients are needed to prove that ticagrelor and prasugrel are just as safe and effective as clopidogrel before clinicians can make informed decisions for choice of P2Y12-I in this patient population.

Topics: Administration, Oral; Adolescent; Adult; Aged; Cardiovascular Diseases; Clinical Decision-Making; Clopidogrel; Drug Prescriptions; Drug Utilization; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Patient Selection; Peritoneal Dialysis; Platelet Aggregation Inhibitors; Practice Patterns, Physicians'; Prasugrel Hydrochloride; Prevalence; Purinergic P2Y Receptor Antagonists; Registries; Renal Dialysis; Retrospective Studies; Risk Assessment; Risk Factors; Ticagrelor; Time Factors; Treatment Outcome; United States; Young Adult

We sought to investigate the utilization of prasugrel and its association with outcomes relative to clopidogrel in three typical subgroups of ACS in a real-world setting. Prasugrel is superior to clopidogrel for reducing risk of ischemic events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI), but is associated with an increased risk of bleeding complications. PROMETHEUS was a retrospective multicenter observational study of 19,913 ACS patients undergoing PCI from 8 centers in the United States between 2010 and 2013. Major adverse cardiovascular events (MACE) were defined as a composite of all-cause mortality, myocardial infarction, stroke or unplanned revascularization. The study cohort included 3285 (16.5%) patients with ST-segment elevation myocardial infarction (STEMI), 5412 (27.2%) patients with NSTEMI and 11,216 (56.3%) patients with unstable angina (UA). The frequency of prasugrel use at discharge was highest in STEMI and lowest in UA patients, 27.3% versus 22.2% versus 18.9% (p < 0.001). Use of prasugrel vs clopidogrel was associated with a lower rate of MACE in STEMI, NSTEMI, or UA at 1 year, but the differences were attenuated for all groups except for patients with UA (adjusted HR 0.81, 95% CI 0.69-0.94, p = 0.006) after propensity adjusted analysis. After adjustment, there was no difference in bleeding risk between prasugrel and clopidogrel for all groups at 1 year. STEMI patients were more likely to receive prasugrel compared to NSTEMI and UA patients. Prasugrel was associated with reduced adverse outcomes compared with clopidogrel in unadjusted analyses, findings that were largely attenuated upon adjustment and suggest preferential use of prasugrel in low vs high risk patients.

Topics: Acute Coronary Syndrome; Aged; Angina, Unstable; Cardiovascular Diseases; Clopidogrel; Female; Hemorrhage; Humans; Male; Middle Aged; Non-ST Elevated Myocardial Infarction; Prasugrel Hydrochloride; Registries; Retrospective Studies; ST Elevation Myocardial Infarction; Treatment Outcome; United States

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

Background Prior reports indicate that the effect of P2Y

Topics: Acute Coronary Syndrome; Aged; Angina, Unstable; Asian People; Cardiovascular Diseases; Cause of Death; Clopidogrel; Female; Hemorrhage; Humans; Male; Middle Aged; Mortality; Myocardial Infarction; Prasugrel Hydrochloride; Proportional Hazards Models; Purinergic P2Y Receptor Antagonists; Recurrence; Republic of Korea; Stroke; Ticagrelor; Treatment Outcome

Topics: Adverse Drug Reaction Reporting Systems; Cardiovascular Diseases; Clopidogrel; Humans; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Ticagrelor; United States; United States Food and Drug Administration

Topics: Adverse Drug Reaction Reporting Systems; Aged; Cardiovascular Diseases; Comorbidity; Data Accuracy; Diabetes Mellitus; Female; Humans; Male; Prasugrel Hydrochloride; Research Design; Risk Assessment; Risk Factors; Ticagrelor; Treatment Outcome; United States; United States Food and Drug Administration

There is little information regarding comparison of ticagrelor and prasugrel in patients with ST-segment elevation myocardial infarction (STEMI). We sought to compare clinical outcomes between ticagrelor and prasugrel in STEMI.Methods and Results:A total of 1,440 patients with STEMI who underwent successful primary percutaneous coronary intervention were analyzed; the data were obtained from the Korea Acute Myocardial Infarction Registry-National Institutes of Health. Of the patients, 963 received ticagrelor, and 477 received prasugrel. The primary study endpoint was 12-month major adverse cardiac events (MACE), including cardiac death, myocardial infarction (MI), and target vessel revascularization (TVR). MACE occurred in 91 patients (6.3%) over the 1-year follow-up, and there were no differences in the incidence of MACE (hazard ratio [HR] 1.20, 95% confidence interval [CI] 0.76-1.91, P=0.438) between the 2 groups. Analysis by propensity score matching (429 pairs) did not significantly affect the results. The incidence of in-hospital major bleeding events was still comparable between the 2 groups (2.4% vs. 2.5%, odds ratio 0.75, 95% CI 0.30-1.86, P=0.532), and there was no significant difference in the incidence of MACE (5.4% vs. 5.8%, HR 0.98, 95% CI 0.56-1.74, P=0.951) after matching.. Ticagrelor and prasugrel showed similar efficacy and safety profiles for treating STEMI in this Korean multicenter registry.

Topics: Aged; Cardiovascular Diseases; Cohort Studies; Female; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Registries; Republic of Korea; ST Elevation Myocardial Infarction; Ticagrelor; Treatment Outcome

Data on the clinical impact of gender in "real-life" patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), receiving clopidogrel, prasugrel, or ticagrelor are limited. We aimed to investigate sex-based differences in clinical outcome of those patients.. In a prospective, observational, multicenter, cohort study, 2047 patients were recruited into the GReekAntiPlatElet (GRAPE) Registry and were followed up until 1 year for major adverse cardiovascular events (MACE, composite of death, nonfatal myocardial infarction, urgent revascularization, and stroke) and bleeding events (Bleeding Academic Research Consortium [BARC] classification).. Women (n=360, 17.6%) were more frequently administered clopidogrel (rather than novel P2Y. In a contemporary "real-life" cohort of patients with ACS treated with PCI and focusing on antiplatelet treatment 1-year ischemic outcome does not differ by gender, while women do present more frequently not actionable bleeding events.

Topics: Acute Coronary Syndrome; Aged; Cardiovascular Diseases; Clopidogrel; Cohort Studies; Female; Greece; Hemorrhage; Humans; Ischemia; Male; Middle Aged; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prospective Studies; Registries; Risk Factors; Sex Characteristics; Stents; Ticlopidine; Treatment Outcome

The reasons for postdischarge adenosine diphosphate receptor inhibitor (ADPri) switching among patients with myocardial infarction (MI) are unclear. We sought to describe the incidence and patterns of postdischarge ADPri switching among patients with acute MI treated with percutaneous coronary intervention.. We used TRANSLATE-ACS (2010-2012) data to assess postdischarge ADPri switching among 8,672 MI patients discharged after percutaneous coronary intervention who remained on ADPri therapy 1 year post-MI. We examined patient-reported reasons for switching, GUSTO moderate or severe bleeding, major adverse cardiovascular events (MACEs), and definite stent thrombosis events around the time of the switch.. Among patients still on ADPri therapy 1 year post-MI, 663 (7.6%) switched ADPri during that year. Switching occurred at a median of 50 days postdischarge and most frequently in patients discharged on ticagrelor (64/226; 28.3%), followed by prasugrel (383/2,489; 15.4%) and clopidogrel (216/5,957; 3.6%) (P < .001). Among patients discharged on prasugrel, 97.3% of switches were to clopidogrel and 87.5% of ticagrelor switches were to clopidogrel; both of these groups most often cited cost as a reason for switching (43.6% and 39.1%, respectively), whereas 60.7% who switched from clopidogrel cited physician decision as a reason. In the 7 days preceding the switch from clopidogrel, 40 (18.5%) had a MACE and 12 (5.6%) had a definite stent thrombosis event, whereas that from prasugrel or ticagrelor, a GUSTO moderate or severe bleeding event occurred in 1 (0.3%) and 0 patients, respectively.. Postdischarge ADPri switching occurred infrequently within the first year post-MI and uncommonly was associated with MACEs or bleeding events.

Topics: Adenosine; Adenosine Diphosphate; Aged; Cardiovascular Diseases; Clopidogrel; Drug Substitution; Female; Hemorrhage; Humans; Longitudinal Studies; Male; Middle Aged; Myocardial Infarction; Patient Discharge; Patient Preference; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P1 Receptor Antagonists; Ticagrelor; Ticlopidine

Despite dual antiplatelet treatment, major ischemic events are common following ST elevation myocardial infarction (STEMI). We aimed to assess high platelet reactivity on aspirin (HPR-aspirin) and its association with P2Y12i (HPR-P2Y12i) during the acute phase of STEMI.. We included all consecutive patients admitted for STEMI treated by primary angioplasty in our center for 1year. All patients received a loading dose followed by a maintenance dose of aspirin (75mg/day) and prasugrel (ticagrelor or clopidogrel if contraindicated). Platelet reactivity was assessed 4±1days and 75±15days after admission using light transmission aggregometry with arachidonic acid (LTA-AA-HPR-aspirin) and VASP (HPR-P2Y12i) to define HPR as well as serum Thromboxane-B2 and LTA-ADP. Major cardiac and cerebrovascular events were recorded for 1year.. We included 106 patients - mean age was 61y.o., 76% were male and 20% had diabetes. STEMI was anterior in 52% and LV ejection fraction at discharge was 51±9%. 50% of patients were treated with prasugrel and 34% with ticagrelor. At day 4 after STEMI, HPR-aspirin was found in 26% patients and HPR-P2Y12i in 7%. HPR- both aspirin and P2Y12i was found in 4%. Diabetes and age were predictors of HPR-aspirin. HPR-aspirin was persistent 75days later in 36% patients. At 1year, 7.9% patients had experienced major adverse cardiovascular and cerebrovascular events (MACCE). HPR-aspirin and HPR on both aspirin and P2Y12i were significantly associated with MACCE.. HPR-aspirin is frequent just after STEMI and associated with MACCE especially when associated with HPR-P2Y12i.

Topics: Acute Disease; Adenosine; Aspirin; Blood Platelets; Brain Ischemia; Cardiovascular Diseases; Clopidogrel; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Prospective Studies; Purinergic P2Y Receptor Antagonists; ST Elevation Myocardial Infarction; Survival Analysis; Ticagrelor; Ticlopidine

Proton pump inhibitors (PPIs) reduce gastrointestinal bleeding events but may alter clopidogrel metabolism. We sought to understand the comparative effectiveness and safety of prasugrel versus clopidogrel in the context of proton pump inhibitor (PPI) use.. Using data on 11 955 acute myocardial infarction (MI) patients treated with percutaneous coronary intervention at 233 hospitals and enrolled in the TRANSLATE-ACS study, we compared whether discharge PPI use altered the association of 1-year adjusted risks of major adverse cardiovascular events (MACE; death, MI, stroke, or unplanned revascularization) and Global Use of Strategies To Open Occluded Arteries (GUSTO) moderate/severe bleeding between prasugrel- and clopidogrel-treated patients. Overall, 17% of prasugrel-treated and 19% of clopidogrel-treated patients received a PPI at hospital discharge. At 1 year, patients discharged on a PPI versus no PPI had higher risks of MACE (adjusted hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.21-1.58) and GUSTO moderate/severe bleeding (adjusted HR 1.55, 95% CI 1.15-2.09). Risk of MACE was similar between prasugrel and clopidogrel regardless of PPI use (adjusted HR 0.88, 95% CI 0.62-1.26 with PPI, adjusted HR 1.07, 95% CI 0.90-1.28 without PPI, interaction P=0.31). Comparative bleeding risk associated with prasugrel versus clopidogrel use differed based on PPI use but did not reach statistical significance (adjusted HR 0.73, 95% CI 0.36-1.48 with PPI, adjusted HR 1.34, 95% CI 0.79-2.27 without PPI, interaction P=0.17).. PPIs did not significantly affect the MACE and bleeding risk associated with prasugrel use, relative to clopidogrel.. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01088503.

Topics: Acute Coronary Syndrome; Aftercare; Aged; Cardiovascular Diseases; Clopidogrel; Comparative Effectiveness Research; Female; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Longitudinal Studies; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Proportional Hazards Models; Proton Pump Inhibitors; Purinergic P2Y Receptor Antagonists; Recurrence; Stroke; Ticlopidine; Treatment Outcome

The purpose of this study was to compare various antiplatelet regimens in patients who experienced increased platelet reactivity on clopidogrel therapy with regards to cardiovascular outcomes, including need for revascularization, myocardial infarction (MI), stroke, and cardiovascular (CV) death.. A retrospective chart review was conducted on patients who received percutaneous coronary intervention (PCI) at the Richard L. Roudebush Veterans Affairs Medical Center and were subsequently prescribed either clopidogrel 75 mg twice daily, prasugrel 10 mg daily, or clopidogrel 75 mg daily with high platelet reactivity between October 1, 2009 and November 30, 2010. Correlations between antiplatelet regimens and prevention of cardiovascular outcomes and bleeding events were evaluated. Groups were evaluated statistically as two separate comparisons; the first comparison being clopidogrel twice daily versus prasugrel and the second comparison being clopidogrel twice daily versus clopidogrel daily in those patients with a P2Y12 test result of less than 50%.. A total of 108 patients were included in the study. Eight events occurred in the clopidogrel twice daily group (n = 26), including five revascularizations and three MIs. Seven events occurred in the prasugrel group (n = 64), including two revascularizations, two MIs, two strokes, and one CV death. The difference between these groups was statistically significant (p = 0.031), with patients in the prasugrel group experiencing fewer events. Five events occurred in the clopidogrel daily group (n = 18), including one need for revascularization, two MIs, and two instances of CV death. There were no statistically significant differences in CV events between the clopidogrel twice daily group and clopidogrel daily group (p > 0.999). There were also no statistically significant differences in bleeding incidents for either of the comparisons; p > 0.999 and p = 0.676 respectively for the first and second comparisons.. Patients on prasugrel had fewer cardiovascular events as compared to patients on clopidogrel twice daily with no difference in bleeding events. No difference was seen with regards to cardiovascular or bleeding events when comparing clopidogrel twice daily to clopidogrel daily in patients with increased platelet reactivity. Study results suggest that there is no benefit to dosing clopidogrel twice daily when compared to either prasugrel or once daily clopidogrel dosing.

Topics: Aged; Cardiovascular Diseases; Clopidogrel; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Retrospective Studies; Stroke; Ticlopidine; United States; United States Department of Veterans Affairs

Topics: Aged; Cardiovascular Diseases; Drug Prescriptions; Humans; Piperazines; Prasugrel Hydrochloride; Prescription Drugs; Purinergic P2Y Receptor Antagonists; Registries; Thiophenes; Treatment Outcome

With increasing usage of Prasugrel (Effient), a new and highly efficient antiplatelet agent, in the management of cardiovascular events, the potential for bleeding complications has also increased. This is further compounded by the lack of a reversal agent, therefore poses a problem for clinicians engaged in oral invasive procedures. A case in which a patient taking daily Prasugrel suffered significantly prolonged bleeding following dental cleaning is reported. Local measures were used to achieve hemostasis. It is prudent to consult the prescribing physician about the risk of Prasugrel-induced bleeding, the potential for recurrence of cardiovascular events with disruption of medication, and the appropriate management strategy in advance of planned oral invasive procedures. Local measures are the first line of approach for management of hemostatic complications associated with Prasugrel, and patients should be referred to specialized centers if local approach fails. As more data become available, further evidence-based guidelines can be established.

Topics: Cardiovascular Diseases; Dental Prophylaxis; Gingival Hemorrhage; Hemostatic Techniques; Humans; Male; Middle Aged; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Thiophenes

Topics: Adenosine; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cardiovascular Diseases; Clopidogrel; Dabigatran; Fibrinolytic Agents; Guideline Adherence; Humans; Morpholines; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thromboembolism; Ticagrelor; Ticlopidine; Treatment Outcome

Abundant thrombin generation may be a major reason for subsequent thromboembolic events in patients with cardiovascular disease receiving dual antiplatelet therapy. We therefore investigated the susceptibility of thienopyridine responders and nonresponders to thrombin receptor-activating peptide (TRAP)-6- and adenosine diphosphate (ADP)-inducible platelet activation.. Response to clopidogrel or prasugrel was determined by the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay and multiple electrode aggregometry (MEA) in 317 patients undergoing angioplasty and stenting for cardiovascular disease. Baseline, TRAP-6-, and ADP-inducible P-selectin expression, activated glycoprotein IIb/IIIa (GPIIb/IIIa) and monocyte-platelet aggregate (MPA) formation were measured as sensitive parameters of platelet activation.. In patients with high on-treatment residual ADP-inducible platelet reactivity (HRPR), baseline P-selectin expression, GPIIb/IIIa and MPA formation were similar to those in patients without HRPR (all P > 0.05). After platelet activation with TRAP-6 or ADP, patients with HRPR by both assays exhibited significantly higher levels of P-selectin expression, GPIIb/IIIa and MPA formation than patients with an adequate thienopyridine-mediated platelet inhibition (all P ≤ 0.02). However, high levels of TRAP-6-inducible P-selectin, GPIIb/IIIa and MPA formation also occurred in 20.4%, 19.1% and 20.1% of the good responders by the VASP assay, and in 19.6%, 16.6% and 20.6% of the good responders by MEA, respectively.. Thienopyridine nonresponders are more susceptible to thrombin- and ADP-inducible platelet activation than patients with good platelet inhibition. However, even patients with adequate thienopyridine-mediated platelet inhibition often show a preserved responsiveness to thrombin. These patients may benefit from additional thrombin receptor blockage or inhibition of thrombin generation.

Topics: Adenosine Diphosphate; Aged; Angioplasty; Aspirin; Blood Platelets; Cardiovascular Diseases; Clopidogrel; Female; Humans; Integrin beta3; Male; Middle Aged; P-Selectin; Peptide Fragments; Piperazines; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Membrane Glycoprotein IIb; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Stents; Thiophenes; Thrombin; Ticlopidine

Patients taking antiplatelet agents for the prevention of cardiovascular diseases who develop gastrointestinal bleeding represent a serious challenge in clinical practice. The initial step in reducing gastrointestinal risk of antiplatelet therapy is to assess whether the patient has a continued need for antiplatelet therapy. The next step is to eliminate the risk factors that may place the patient at increased gastrointestinal risk. In the management of bleeding ulcer patients with high-risk stigmata of recent hemorrhage, resuming antiplatelet agents at 3-5 days after the last dosing is a reasonable strategy. However, patients with low-risk stigmata can keep taking antiplatelet agents immediately following endoscopy. In the management of aspirin-related uncomplicated peptic ulcers in patients requiring antiplatelet therapies, continuing aspirin plus a powerful proton pump inhibitor is the choice of treatment. Patients who require antiplatelet agents for the prevention of cardiovascular diseases should be tested and treated for Helicobacter pylori infection before starting antiplatelet therapy. Additionally, those with high risks for upper gastrointestinal bleeding should receive co-therapy with a gastroprotective drug, preferably a proton pump inhibitor at standard dose. H2-receptor antagonist can significantly reduce upper gastrointestinal bleeding risk in patients taking low-dose aspirin but it is ineffective in the prevention of upper gastrointestinal bleeding in clopidogrel users. Although several retrospective studies reported that patients prescribed clopidogrel who also took proton pump inhibitors had significant increases in cardiovascular events, the current evidence from a prospective randomized trial does not justify a conclusion that proton pump inhibitors are associated with cardiovascular events among clopidogrel users.

Topics: Aspirin; Cardiovascular Diseases; Clopidogrel; Drug Interactions; Gastrointestinal Hemorrhage; Helicobacter Infections; Helicobacter pylori; Humans; Peptic Ulcer; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Proton Pump Inhibitors; Thiophenes; Ticlopidine

Topics: Angioplasty, Balloon; Angioplasty, Balloon, Coronary; Blood Platelets; Cardiovascular Diseases; Coronary Artery Disease; Female; Humans; Male; Myocardial Infarction; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Stents; Thiophenes; Tirofiban; Tyrosine

To estimate the cost-effectiveness of genotype-guided selection of antiplatelet therapy compared with selecting clopidogrel or prasugrel irrespective of genotype.. Decision model based on event occurrence in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38.. Simulated cohort of patients with acute coronary syndrome scheduled to undergo percutaneous coronary intervention (PCI), consisting of three arms: those receiving genotype-guided antiplatelet therapy with clopidogrel or prasugrel, those receiving clopidogrel regardless of genotype, and those receiving prasugrel regardless of genotype.. All three arms of the model incorporated the probability that patients would experience a cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke), a bleeding event (major or minor bleeding), or no event while receiving antiplatelet therapy during the 15 months after the scheduled PCI. The cytochrome P450 (CYP) 2C19 genotype determined antiplatelet drug selection in the genotyping group. Cost-effectiveness was expressed as the incremental cost-effectiveness ratio (ICER) for each event avoided in the genotype-guided therapy arm versus the other two arms. Genotype-guided antiplatelet therapy was dominant, or more effective and less costly, when compared with the selection of clopidogrel (ICER -$6760 [95% confidence interval (CI) -$6720 to -$6790]) or prasugrel (ICER -$11,710 [95% CI -$11,480 to -$11,950]) for all patients without regard to genotype. Genotype-guided therapy that included generic clopidogrel was dominant to prasugrel for all patients (ICER -$27,160 [95% CI -$27,890 to -$26,420]). Cost savings were not evident when genotype-guided therapy that included generic clopidogrel was compared with generic clopidogrel for all patients (ICER $2300 [95% CI $2290 to $2320]). [Correction added after online publication 12-Mar-2012: In the previous sentence -$2300 has been corrected as $2300.].. Genotype-guided antiplatelet therapy selection may be more cost-effective and may provide more clinical value due to fewer adverse outcomes.

Topics: Acute Coronary Syndrome; Aryl Hydrocarbon Hydroxylases; Cardiovascular Diseases; Clopidogrel; Computer Simulation; Cost-Benefit Analysis; Cytochrome P-450 CYP2C19; Decision Trees; Drugs, Generic; Genotype; Hemorrhage; Humans; Models, Economic; Models, Statistical; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes; Thrombolytic Therapy; Ticlopidine

Topics: Adenosine; Cardiovascular Diseases; Clopidogrel; Humans; Percutaneous Coronary Intervention; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes; Ticagrelor; Ticlopidine

Central adjudication in randomised controlled outcome-driven trials represents a traditional approach to maintain data integrity by applying uniformed rules for assessment of clinical events. It was the purpose of this investigation to determine the patterns of myocardial infarction (MI) adjudication in the TRITON, RECORD, and PLATO trials. We were matching centrally-adjudicated MI's (CAMI's) from the official trial publication with the site-reported MI (SRMI's) count from the Food and Drug Administration's secondary analyses for the investigational compounds prasugrel (TRITON), rosiglitazone (RECORD), and ticagrelor (PLATO). CAMI numbers showed a remarkable discrepancy to SRMI's by more than a doubling of the difference: from 72 to 145 events in TRITON favoring prasugrel (from a hazard ratio [HR]=0.76, p=0.08; to a HR=0.76, p<0.001), and from 44 to 89 events in favour of ticagrelor in PLATO (from a HR=0.94, p=0.095; to a HR=0.84, p<0.001). In contrast, in the RECORD trial, the CAMI count was less than the SRMI count (from 24 to 8 events, from a HR=1.42, p=0.93; to a HR=1.14, p=0.96), in this case diminishing cardiovascular hazards in favour of rosiglitazone. In conclusion, central adjudication in the TRITON, the RECORD, and the PLATO trial turned out to have a critical impact on study outcomes. Trial publications should in the future include site-reported major efficacy and safety endpoints to preserve data integrity. The regulatory authorities should consider independent audits when there is a major disagreement between centrally adjudicated and site reported events influencing the results of a major clinical trial.

Topics: Acute Coronary Syndrome; Adenosine; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Judgment; Metformin; Multicenter Studies as Topic; Myocardial Infarction; Observer Variation; Outcome Assessment, Health Care; Percutaneous Coronary Intervention; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Process Assessment, Health Care; Randomized Controlled Trials as Topic; Rosiglitazone; Stroke; Sulfonylurea Compounds; Thiazolidinediones; Thiophenes; Ticagrelor

One possible cause of stent thrombosis is an insufficient effect of clopidogrel. In a prospective study, we aimed to optimize the platelet inhibition of clopidogrel low responders (CLR) by multiple electrode platelet aggregometry (MEA)-guided therapy modifications and to evaluate specific major adverse cardiac and cerebrovascular events (MACCE).. ADP-induced platelet aggregation was measured by MEA in 1,005 consecutive patients after stent implantation and 600 mg clopidogrel loading dose. All patients received at least 100 mg aspirin/day. In 118 patients (11.7%), ADP values remained in the reference range generated in 150 controls and were defined as CLR. Significant independent predictors of CLR were acute coronary syndrome (ACS) (OR = 6.54), diabetes (OR = 2.07), use of diuretics (OR = 1.93) or proton pump inhibitors (OR = 1.64) and male gender (OR = 1.83). Ninety-nine CLR were switched to clopidogrel 150 mg/day, leading to an adequate response in 54/99. Subsequently, 44 patients were changed to ticlopidine 2 × 250 mg/day, resulting in an inhibition in 24/44. The remaining 20 patients received 2 × 100 mg cilostazol/day in addition to 75 mg clopidogrel/day. After its recent availability, 19/118 primary CLR were treated with 5-10 mg prasugrel/day. One patient was a prasugrel low responder. The total thienopyridine low response-rate was 2% in our population. The specific MACCE rate (death, non-fatal target vessel myocardial infarction, non-fatal stroke) of the CLR under optimized treatment (except prasugrel) was 2.0% at 30 days and 3.0% during a mean follow-up of 44 weeks.. Clopidogrel low response is present in 1/10 patients and more frequent in ACS-PCI. MEA-guided optimizing of thienopyridine therapy is feasible and results in a very low specific MACCE rate. Low response to all thienopyridines is rare.

Topics: Adenosine Diphosphate; Aged; Angioplasty, Balloon, Coronary; Cardiovascular Diseases; Cerebrovascular Disorders; Cilostazol; Clopidogrel; Drug Monitoring; Drug Resistance; Drug Substitution; Electrodes; Female; Germany; Humans; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Predictive Value of Tests; Prospective Studies; Risk Assessment; Risk Factors; Stents; Tetrazoles; Thiophenes; Thrombosis; Ticlopidine; Time Factors; Treatment Outcome

Topics: Administration, Oral; Cardiovascular Diseases; Clopidogrel; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes; Ticlopidine

The FDA has approved ticagrelor (Brilinta-AstraZeneca), an oral antiplatelet drug, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (Plavix) and prasugrel (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months.

Topics: Adenosine; Aspirin; Cardiovascular Diseases; Clopidogrel; Drug Approval; Drug Interactions; Drug Therapy, Combination; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Randomized Controlled Trials as Topic; Thiophenes; Ticagrelor; Ticlopidine; United States

The response to thienopyridine antiplatelet therapy is heterogeneous and is in part explained by clinical and genetic factors. A recent meta-analysis has demonstrated the clinical significance of a genetic polymorphism in the cytochrome P450 2C19 gene. Carriers of this polymorphism have a higher incidence of stent thrombosis and cardiovascular death, whilst on the thienopyridine clopidogrel. The polymorphism and rarer variants display higher carrier frequencies in ethnic groups with disproportionate cardiovascular mortality, such as Māori. Knowledge of an individual's genetic status may assist in optimising antiplatelet therapy, thereby reducing the cost of adverse events, expenditure on new medicines, and the ethnic disparities seen in healthcare outcomes. A demonstration of the cost-effectiveness of genetic testing, on a population basis, and a proven alternative, personalised strategy is required before the adoption of this technology can be advocated.

Topics: Aryl Hydrocarbon Hydroxylases; Cardiovascular Diseases; Clopidogrel; Cytochrome P-450 CYP2C19; Genetic Markers; Genetic Testing; Humans; Native Hawaiian or Other Pacific Islander; Pharmacogenetics; Piperazines; Platelet Aggregation Inhibitors; Polymorphism, Genetic; Prasugrel Hydrochloride; Precision Medicine; Stents; Thiophenes; Thrombosis; Ticlopidine; Vascular Diseases

Clopidogrel and prasugrel are subject to efflux via P-glycoprotein (encoded by ABCB1, also known as MDR1). ABCB1 polymorphisms, particularly 3435C→T, may affect drug transport and efficacy. We aimed to assess the effect of this polymorphism by itself and alongside variants in CYP2C19 on cardiovascular outcomes in patients treated with clopidogrel or prasugrel in TRITON-TIMI 38. We also assessed the effect of genotype on the pharmacodynamic and pharmacokinetic properties of these drugs in healthy individuals.. We genotyped ABCB1 in 2932 patients with acute coronary syndromes undergoing percutaneous intervention who were treated with clopidogrel (n=1471) or prasugrel (n=1461) in the TRITON-TIMI 38 trial. We evaluated the association between ABCB1 3435C→T and rates of the primary efficacy endpoint (cardiovascular death, myocardial infarction, or stroke) until 15 months. We then assessed the combined effect of ABCB1 3435C→T genotype and reduced-function alleles of CYP2C19. 321 healthy individuals were also genotyped, and we tested the association of genetic variants with reduction in maximum platelet aggregation and plasma concentrations of active drug metabolites.. In patients treated with clopidogrel, ABCB1 3435C→T genotype was significantly associated with the risk of cardiovascular death, myocardial infarction, or stroke (p=0·0064). TT homozygotes had a 72% increased risk of the primary endpoint compared with CT/CC individuals (Kaplan-Meier event rates 12·9% [52 of 414] vs 7·8% [80 of 1057 participants]; HR 1·72, 95% CI 1·22-2·44, p=0·002). ABCB1 3435C→T and CYP2C19 genotypes were significant, independent predictors of the primary endpoint, and 681 (47%) of the 1454 genotyped patients taking clopidogrel who were either CYP2C19 reduced-function allele carriers, ABCB1 3435 TT homozygotes, or both were at increased risk of the primary endpoint (HR 1·97, 95% CI 1·38-2·82, p=0·0002). In healthy participants, 3435 TT homozygotes had an absolute reduction in maximum platelet aggregation with clopidogrel that was 7·3 percentage points less than for CT/CC individuals (p=0·0127). ABCB1 genotypes were not significantly associated with clinical or pharmacological outcomes in patients with an acute coronary syndrome or healthy individuals treated with prasugrel, respectively.. Individuals with the ABCB1 3435 TT genotype have reduced platelet inhibition and are at increased risk of recurrent ischaemic events during clopidogrel treatment. In patients with acute coronary syndromes who have undergone percutaneous intervention, when both ABCB1 and CYP2C19 are taken into account, nearly half of the population carries a genotype associated with increased risk of major adverse cardiovascular events while on standard doses of clopidogrel.. Daiichi Sankyo Company Ltd and Eli Lilly and Company.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Aryl Hydrocarbon Hydroxylases; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cardiovascular Diseases; Clopidogrel; Cytochrome P-450 CYP2C19; Female; Genetic Variation; Genotype; Humans; Male; Middle Aged; Pharmacogenetics; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Polymorphism, Single Nucleotide; Prasugrel Hydrochloride; Randomized Controlled Trials as Topic; Thiophenes; Ticlopidine

Topics: Administration, Oral; Angioplasty, Balloon, Coronary; Animals; Aspirin; Blood Platelets; Cardiovascular Diseases; Clinical Trials as Topic; Clopidogrel; Drug Administration Schedule; Drug Resistance; Hemorrhage; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Research Design; Risk Assessment; Stents; Thiophenes; Ticlopidine; Treatment Outcome

Topics: Adolescent; Adolescent Nutritional Physiological Phenomena; American Heart Association; Cardiovascular Diseases; Cholesterol; Congresses as Topic; Coronary Artery Disease; Drug Approval; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Obesity; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Randomized Controlled Trials as Topic; Thiophenes; United States

Both clopidogrel and prasugrel require biotransformation to active metabolites by cytochrome P450 (CYP) enzymes. Among persons treated with clopidogrel, carriers of reduced-function CYP2C19 alleles have significantly lower levels of active metabolite, diminished platelet inhibition, and higher rates of adverse cardiovascular events. The effect of CYP polymorphisms on the clinical outcomes in patients treated with prasugrel remains unknown.. The associations between functional variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to prasugrel were tested in 238 healthy subjects. We then examined the association of these genetic variants with cardiovascular outcomes in a cohort of 1466 patients with acute coronary syndromes allocated to treatment with prasugrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 trial. Among the healthy subjects, no significant attenuation of the pharmacokinetic or the pharmacodynamic response to prasugrel was observed in carriers versus noncarriers of at least 1 reduced-function allele for any of the CYP genes tested (CYP2C19, CYP2C9, CYP2B6, CYP3A5, and CYP1A2). Consistent with these findings, in subjects with acute coronary syndromes treated with prasugrel, no significant associations were found between any of the tested CYP genotypes and risk of cardiovascular death, myocardial infarction, or stroke.. Common functional CYP genetic variants do not affect active drug metabolite levels, inhibition of platelet aggregation, or clinical cardiovascular event rates in persons treated with prasugrel. These pharmacogenetic findings are in contrast to observations with clopidogrel, which may explain, in part, the different pharmacological and clinical responses to the 2 medications.

Topics: Adult; Aged; Aryl Hydrocarbon Hydroxylases; Biotransformation; Cardiovascular Diseases; Cytochrome P-450 CYP2C19; Cytochrome P-450 Enzyme System; Female; Genotype; Humans; Male; Microsomes, Liver; Middle Aged; Myocardial Infarction; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Polymorphism, Genetic; Prasugrel Hydrochloride; Prodrugs; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Stroke; Thiophenes; Treatment Outcome; Young Adult

Topics: Anticoagulants; Cardiovascular Diseases; Clinical Trials as Topic; Clopidogrel; Female; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; Genome-Wide Association Study; Genomics; Humans; Pharmacogenetics; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes; Ticlopidine; Warfarin

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Aspirin; Cardiovascular Diseases; Causality; Clinical Trials as Topic; Combined Modality Therapy; Coronary Thrombosis; Drug Administration Schedule; Drug Therapy, Combination; Hemorrhage; Humans; Myocardial Infarction; Neoplasms; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes; United States; United States Food and Drug Administration

(1) For patients with acute coronary syndromes who have undergone percutaneous angioplasty and stenting, the best-assessed treatment for preventing relapses is a combination of aspirin and clopidogrel; (2) Prasugrel, an antiplatelet drug belonging the same chemical class as clopidogrel, is authorized in the EU for use in this indication; (3) Clinical evaluation is based on a randomized double-blind trial comparing prasugrel + aspirin versus clopidogrel + aspirin in 13 608 patients with acute coronary syndromes, half of whom were treated for at least 15 months. Prasugrel did not reduce overall mortality (about 3%) or the incidence of non-fatal stroke after 15 months (1% of patients). The only advantage reported with prasugrel was a significant reduction in the risk of non-fatal myocardial infarction (7.3% versus 9.5%); (4) In this trial, bleeding events, excluding those related to revascularisation procedures, were more frequent in the prasugrel group than in the clopidogrel group (2.4% versus 1.8%). Haemorrhages associated with revascularisation were also significantly more numerous with prasugrel (11.3% and 3.6%); (5) Subgroup analyses suggest that the risk-benefit balance of prasugrel is unfavourable in patients weighing less than 60 kg, patients over 75 years of age, and patients with a history of transient ischaemic attack or stroke; (6) The trial comparing prasugrel versus clopidogrel, as well as some animal studies, raise the possibility that prasugrel might increase the risk of cancer. In the main trial, prasugrel caused fewer cases of neutropenia than clopidogrel, but more cases of respiratory failure, hypotension and atrial flutter were observed; (7) In practice, for secondary prevention in patients with acute coronary syndromes treated with angioplasty and stenting, the risk-benefit balance of prasugrel, used in combination with aspirin, appears to be no better than that of clopidogrel + aspirin.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Aspirin; Cardiovascular Diseases; Clopidogrel; Double-Blind Method; Drug Therapy, Combination; Drug-Eluting Stents; Europe; Hemorrhage; Humans; Ischemic Attack, Transient; Myocardial Infarction; Neoplasms; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Randomized Controlled Trials as Topic; Receptors, Purinergic P2; Recurrence; Stents; Stroke; Thiophenes; Ticlopidine; Treatment Outcome

Topics: Animals; Cardiovascular Diseases; Clinical Trials as Topic; Drug Approval; Humans; Membrane Proteins; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Thiophenes; Treatment Outcome