prasugrel-hydrochloride and Thrombosis

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

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

To evaluate the outcomes, safety, and efficacy of dual antiplatelet therapy (DAPT) with newer P2Y. Eight studies (1 randomized trial and 7 cohort studies) comprising 1100 patients (695 [63.2%] receiving clopidogrel and 405 [36.8%] receiving ticagrelor or prasugrel) were included. The population was mostly male (68.5%-86.7%). Risk of bias was low for these studies, with between-study heterogeneity and subgroup differences not statistically significant. Compared with the clopidogrel cohort, the newer P2Y. In patients with AMI-CA/CS receiving DAPT, compared with clopidogrel, newer P2Y

Topics: Clopidogrel; Female; Heart Arrest; Hemorrhage; Humans; Male; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Shock, Cardiogenic; Thrombosis; Treatment Outcome

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

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

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

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

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

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

Dual antiplatelet therapy (DAPT) is the treatment of choice in the medical management of patients with acute coronary syndrome (ACS). The combination of aspirin and a P2Y12 inhibitor in patients who receive a coronary stent reduces the rate of stent thrombosis and the rates of major adverse cardiovascular events. However, patients with acute coronary syndrome remain at risk of recurrent cardiovascular events despite the advance of medical therapy. The limitations of clopidogrel with variable antiplatelet effects and delayed onset of action are well established and lead to the development of newer P2Y12 inhibitors. Prasugrel is a selective adenosine diphosphate (ADP) receptor antagonist indicated for use in patients with ACS. Prasugrel provides greater inhibition of platelet aggregation than clopidogrel and has a rapid onset of action. We have conducted a systematic review to retrieve current evidence regarding the role of prasugrel in the management of ACS. Evidence comparing prasugrel, clopidogrel, and ticagrelor remain scant.. A complete literature survey was performed using PubMed database search to gather available information regarding management of acute coronary syndromes and prasugrel. An explorative comparison of the safety and efficacy of prasugrel, clopidogrel, and ticagrelor was also conducted.. Prasugrel and ticagrelor are more efficacious than clopidogrel in reducing the occurrence of non-fatal myocardial infarction, stroke, or cardiovascular (CV) death but they have also an increased risk of major bleeding in comparison to clopidogrel.. Prasugrel and ticagrelor are today the recommended first-line agents in patients with ACS. The estimation of which drug is superior over the other cannot be reliably established from the current trials.

Topics: Acute Coronary Syndrome; Aspirin; Clopidogrel; Hemorrhage; Humans; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thrombosis; 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

Despite the demonstrated benefits of Prasugrel, a new generation thienopyridine, in the prevention of thrombotic complications after percutaneous coronary interventions (PCI) for Acute Coronary Syndromes (ACS), its use is still precluded to those many patients arriving to the cath lab pre-treated with Clopidogrel. Conclusive data on the strategy of switching from Clopidogrel to Prasugrel are still missing, therefore we aimed to perform a meta-analysis of current studies evaluating the safety and efficacy of switching from Clopidogrel to Prasugrel (PS) as compared to a standard thienopyridine therapy with Clopidogrel or Prasugrel in patients undergoing PCI. Literature archives and main scientific sessions' abstracts were scanned for studies comparing a switching strategy from Clopidogrel to Prasugrel vs. Prasugrel or Clopidogrel. Primary efficacy endpoint was overall mortality. Secondary endpoints were: non-fatal myocardial infarction and definite/probable stent thrombosis. Safety endpoint was the rate of major bleedings according to a per-protocol definition. A total of 12 studies, involving 3956 patients, were included. Among them, 1396 patients (35.3%), received Prasugrel after a Clopidogrel treatment (PS), while 2560 (64.7%) received either Prasugrel or Clopidogrel. The switch from Clopidogrel to Prasugrel was in the majority of the studies periprocedural. The mortality was numerically lower, but not statistically significant, in the PS group as compared with patients who did not switch (1.7% vs. 3.8%, OR [95% CI] = 0.68 [0.40,1.15], p = 0.15, phet = 0.61), without any relationship with patients' risk profile (r = -0.68 [-2.09, 0.73], p = 0.35). Similar results were obtained for secondary efficacy endpoints and at sensitivity analysis in the majority of subgroups evaluated. Moreover, the PS strategy did not increase major bleedings as compared with standard therapy (1.4% vs. 2.5%, OR [95% CI = 0.70 [0.39, 1.25], p = 0.23, phet = 0.6). The present meta-analysis confirms that, among patients undergoing PCI, switching from Clopidogrel to Prasugrel may be safely performed and therefore should be encouraged among patients eligible to Prasugrel.

Topics: Acute Coronary Syndrome; Clopidogrel; Drug Substitution; Hemorrhage; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Survival Analysis; Thrombosis; Ticlopidine; Treatment Outcome

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

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

Dual antiplatelet therapy (DAPT) with aspirin combined with either a thienopyridine (clopidogrel or prasugrel) or acyclopentyl-triazolo-pyrimidine (ticagrelor) plays a vital role in the management of acute coronary syndrome (ACS) especially in those undergoing percutaneous coronary intervention (PCI) but even those being managed medically. Observational studies and some formal studies have shown patients on the standard dual antiplatelet regimen (clopidogrel and aspirin) continue to have further ischemic events and can suffer stent thrombosis. It has been demonstrated that clopidogrel is associated with a delayed onset of action with a considerable inter-individual variation to treatment thus making it difficult to achieve an optimal level of platelet inhibition. Areas covered: This article will review the current evidence that is available regarding the effectiveness and safety of prasugrel in ACS patients undergoing percutaneous coronary intervention (PCI). Expert commentary: Prasugrel is an oral third-generation inhibitor of platelet activation and aggregation. Laboratory studies and early phase clinical trials show prasugrel has a faster onset of action, is more potent and has reduced inter-patient response variability compared to clopidogrel. The published studies so far demonstrated that prasugrel when compared to clopidogrel also shows a higher degree of effectiveness in the prevention of platelet-initiated thrombotic events in patients with ACS undergoing PCI, however these benefits are offset somewhat by an increased bleeding risk.

Topics: Acute Coronary Syndrome; Administration, Oral; Aspirin; Blood Platelets; Clopidogrel; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Activation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thrombosis; Ticlopidine

Whether prasugrel can take the place of clopidogrel for patients with acute coronary syndrome (ACS) is not clear. The aim of this study was to perform a meta-analysis for systematically reviewing the evidence on prasugrel in comparison to clopidogrel in patients with ACS.. Relevant prospective and retrospective studies were searched in databases. Six studies were finally included. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to assess all causes of death, myocardial infarction (MI), stroke, major bleeding, major/minor bleeding, and stent thrombosis (for PCI performed).. Compared with clopidogrel, prasugrel had similar risks of all cause of death (Pooled RR: 0.83; 95% CI: 0.64-1.06, p=0.14, I2=55%), MI (Pooled RR: 0.86; 95% CI: 0.71-1.04, p=0.12) and stroke (pooled RR: 0.88; 95% CI: 0.70-1.10, p=0.25). However, prasugrel was associated with significantly higher risk of both major bleeding (Pooled RR: 1.19; 95% CI: 0.99-1.44, p=0.06, I2=0%) and the risk of total major and minor bleeding (Pooled RR: 1.30; 95% CI: 1.15-1.48, p<0.0001, I2=0%). For the patients who underwent percutaneous coronary intervention (PCI), prasugrel was associated with significantly lower risk of stent thrombosis (Pooled RR: 0.47; 95% CI: 0.34-0.61, p<0.00001, I2=0%).. Prasugrel has similar effects as clopidogrel in terms of all causes of death, MI, and stroke in ACS patients. For the patients who underwent PCI, prasugrel contributes to lower risk of stent thrombosis. However, prasugrel is associated with significantly higher risk of bleeding. For the patients with active pathological bleeding or a history of stroke and/or TIA, prasugrel should not be recommended.

Topics: Acute Coronary Syndrome; Administration, Oral; Clopidogrel; Evidence-Based Medicine; Hemorrhage; Humans; Myocardial Infarction; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prospective Studies; Purinergic P2Y Receptor Antagonists; Retrospective Studies; Risk Factors; Stroke; Thrombosis; Ticlopidine

Although platelet reactivity during P2Y12-inhibitors is associated with stent thrombosis (ST) and bleeding, standardized and clinically validated thresholds for accurate risk stratification after percutaneous coronary intervention (PCI) are lacking. We sought to determine the prognostic value of low platelet reactivity (LPR), optimal platelet reactivity (OPR), or high platelet reactivity (HPR) by applying uniform cut-off values for standardized devices.. Authors of studies published before January 2015, reporting associations between platelet reactivity, ST, and major bleeding were contacted for a collaborative analysis using consensus-defined, uniform cut-offs for standardized platelet function assays. Based on best available evidence for each device (exploratory studies), LPR-OPR-HPR categories were defined as <95, 95-208, and >208 PRU for VerifyNow, <19, 19-46, and >46 U for the Multiplate analyser and <16, 16-50, and >50% for VASP assay. Seventeen studies including 20 839 patients were used for the analysis; 97% were treated with clopidogrel and 3% with prasugrel. Patients with HPR had significantly higher risk for ST [risk ratio (RR) and 95% CI: 2.73 (2.03-3.69), P < 0.00001], yet a slight reduction in bleeding [RR: 0.84 (0.71-0.99), P = 0.04] compared with those with OPR. In contrast, patients with LPR had a higher risk for bleeding [RR: 1.74 (1.47-2.06), P < 0.00001], without any further benefit in ST [RR: 1.06 (0.68-1.65), P = 0.78] in contrast to OPR. Mortality was significantly higher in patients with HPR compared with other categories (P < 0.05). Validation cohorts (n = 14) confirmed all results of exploratory studies (n = 3).. Platelet reactivity assessment during thienopyridine-type P2Y12-inhibitors identifies PCI-treated patients at higher risk for mortality and ST (HPR) or at an elevated risk for bleeding (LPR).

Topics: Aged; Clopidogrel; Female; Graft Occlusion, Vascular; Hemorrhage; Humans; Male; Percutaneous Coronary Intervention; Platelet Activation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Risk Assessment; Stents; Thrombosis; Ticlopidine

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

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

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

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

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

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

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

Prasugrel, a third-generation thienopyridine antiplatelet agent, demonstrated superior efficacy to clopidogrel but with an increased risk of bleeding in the phase III pivotal registration Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38). This article reviews and discusses select components of a large literature of prasugrel data that has emerged since the TRITON-TIMI 38 (TRITON) study primary disclosure.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Drug Interactions; Drug Resistance; Evidence-Based Medicine; Hemorrhage; Humans; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Thiophenes; Thrombosis; Time Factors; Treatment Outcome

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

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

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

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

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

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

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

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

Dual antiplatelet therapy with aspirin and clopidogrel is routinely used to prevent thrombotic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI) in Japan. However, these agents have various limitations and some patients will experience further cardiovascular events. The purpose of this article is to review the antiplatelet agents currently used in patients undergoing PCI in Japan, to discuss the issues and limitations associated with these antiplatelet agents, and to characterize new antiplatelet agents currently under investigation in Japan. Particular emphasis is placed on the novel thienopyridine prasugrel, and the potential this drug has for overcoming the issues associated with other antiplatelet agents.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Thiophenes; Thrombosis

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

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

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

Atherothrombosis--defined as atherosclerotic lesion disruption with superimposed thrombus formation--is a leading cause of death in patients with diabetes mellitus. Platelets play a pivotal role in atherothrombosis and platelets of diabetic patients are hyperreactive. Numerous studies have investigated the usefulness of antiplatelet therapy for primary and secondary prevention of atherothrombotic events in diabetic patients. However, there are limited evidences that aspirin may be effective in the reduction of atherothrombotic complication in this population. Additionally, dual antiplatelet therapy with aspirin and clopidogrel has been suggested to be harmful. In contrast, the role of antiplatelet therapy in secondary prevention after ischemic cardiac events is well established in diabetes. Glycoprotein IIb/IIIa receptor antagonists can reduce mortality in diabetic patients committed to undergo percutaneous coronary intervention (PCI). Upregulation of P2Y(12) signalling occurs in hyperglycemia, and the relevance of platelet P2Y(12) receptor inhibition with prasugrel in reducing adverse events following PCI has been recently suggested. Besides platelet activation, several other mechanisms may be involved in the pathophysiology of diabetic atherothrombosis. Tissue factor (TF)-bearing procoagulant microparticles (MPs) are a heterogeneous population of membrane-coated vesicles released by several cell lines upon activation or apoptosis. There is converging evidence that MPs and MP-associated TF activity are upregulated in patients with diabetes mellitus and can participate actively in promoting atherothrombotic complications. In this context, drugs that may reduce the release of microparticles and/or their thrombogenic capacity has the potential to improve upon current antiplatelet therapy, possibly resulting in lower adverse events rates in diabetic individuals.

Topics: Acute Coronary Syndrome; Apoptosis; Aspirin; Blood Platelets; Clopidogrel; Diabetes Complications; Diabetes Mellitus; Glycoproteins; Humans; Models, Biological; Piperazines; Platelet Activation; Prasugrel Hydrochloride; Receptors, Purinergic P2Y12; Thiophenes; Thromboplastin; Thrombosis; Ticlopidine

Both clopidogrel and aspirin have been shown to decrease the rate of cardiovascular events and especially stent thrombosis in patients undergoing percutaneous coronary intervention (PCI). However, recent studies have suggested that there is large inter-individual response variability to these drugs (especially to clopidogrel) and that improved inhibition of platelet reactivity using higher doses or new, more potent agents would further reduce the occurrence of cardiovascular events, but may also increase the risk of bleeding. Many different protocols of antiplatelet therapy have been studied and have shown benefit in reducing the rate of major adverse cardiovascular events after PCI. Therefore, the choice of an appropriate antiplatelet therapy protocol is sometimes difficult for the clinician and should be individualized as per the particular patient risk, accounting for both the risk of recurrent cardiovascular events and bleeding. We review the recent data on efficacy and safety of dosing strategies for antiplatelet therapy in PCI.

Topics: Angioplasty, Balloon, Coronary; Aspirin; Clinical Protocols; Clopidogrel; Drug Administration Schedule; Drug Monitoring; Hemorrhage; Humans; Patient Selection; Piperazines; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Risk Assessment; Risk Factors; Thiophenes; Thrombosis; Ticlopidine; Treatment Outcome

To assess the potential role of prasugrel in the management of acute coronary syndrome (ACS) in older adults.. PubMed and International Pharmaceutical Abstracts searches (1966 to 2009) were conducted to identify pertinent English-language studies on the use of prasugrel.. All human studies evaluating pharmacokinetic/pharmacodynamic or clinical efficacy of prasugrel were evaluated.. Prasugrel is a third-generation thienopyridine antiplatelet agent. Other thienopyridine antiplatelet agents (e.g., clopidogrel, ticlopidine) have been associated with interindividual variability, drug-drug interactions, and unfavorable adverse effect profile. Prasugrel therapy is associated with more profound platelet inhibition and improved cardiovascular (CV) outcomes compared with clopidogrel; however, prasugrel therapy is associated with an increased bleeding risk. Prasugrel should not be used in adults older than 75 years of age, those who have had a recent transient ischemic attack (TIA) or stroke, those who have a low body weight < 60 kg, and those receiving medications or having conditions associated with a bleeding risk unless they are at a high risk for a CV event.. Prasugrel therapy does not appear to be associated with interindividual variability in platelet aggregation and has superior CV outcomes compared with clopidogrel. No dosage adjustments need to be made for renal or hepatic impairment. Prasugrel shows promise for the treatment of ACS patients with clopidogrel resistance or those who have an increased risk of CV events (e.g., patients with diabetes); head-to-head trials evaluating these uses have not been conducted. Geriatric patients have an increased risk of bleeding with this agent. Additional studies need to be conducted to determine the appropriate population for prasugrel.

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Clinical Trials as Topic; Drug Interactions; Drug Resistance; Evidence-Based Medicine; Female; Hemorrhage; Humans; Male; Middle Aged; Patient Selection; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Risk Assessment; Risk Factors; Thiophenes; Thrombosis; Treatment Outcome

Topics: Acute Coronary Syndrome; Clinical Trials as Topic; Clopidogrel; Humans; Piperazines; Platelet Activation; Platelet Adhesiveness; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Stents; Thiophenes; Thrombosis; Ticlopidine; Treatment Outcome

Oral antiplatelet therapy with aspirin and clopidogrel is a major strategy to prevent thrombotic events in patients with acute coronary syndromes and patients undergoing percutaneous coronary interventions. Although this therapy is associated with both short- and long-term clinical efficacy, irreversible platelet inhibition and ischemic events associated with premature withdrawal especially in patients treated with drug-eluting stents constitute a particular limitation in patients undergoing surgery. The current review article is focused on the central role of platelets in the occurrence of ischemic events, the significance of antiplatelet therapy, the potential hazards of drug withdrawal in patients needing coronary artery bypass grafting, and future perspectives.

Topics: Administration, Oral; Aspirin; Clinical Trials as Topic; Clopidogrel; Coronary Artery Bypass; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Thiophenes; Thrombosis; Ticlopidine

The administration of dual antiplatelet therapy with aspirin and a thienopyridine for the prevention of thrombosis in patients with acute coronary syndrome undergoing percutaneous coronary intervention is proven to reduce mortality. The original thienopyridine, ticlopidine, has largely been displaced by clopidogrel, which has a superior adverse effect profile. Prasugrel is a new thienopyridine that has been purported to have a faster onset of activity, a lower rate of nonresponders and a greater potency than clopidogrel.. This review compares the metabolism of clopidogrel and prasugrel by carboxylesterases and the CYP system with emphasis on the formation of their respective active metabolites.. The reader will gain an understanding of the pharmacokinetics of prasugrel and clopidogrel and how the differences in their respective metabolic pathways explain the difference in their therapeutic activity.. The superior therapeutic profile of prasugrel is explained by the different roles of carboxylesterases in their metabolic pathways. Though prasugrel is superior to clopidogrel as a prodrug of the active P(2)Y(12) inhibitor, caution is advised because limited information is available on genetic polymorphisms or drug interactions affecting carboxylesterase metabolism.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Aspirin; Carboxylic Ester Hydrolases; Clopidogrel; Cytochrome P-450 Enzyme System; Drug Therapy, Combination; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prodrugs; Thiophenes; Thrombosis; Ticlopidine

The role of platelets in atherothrombotic disease is well established, and antiplatelet therapy is now recommended for the shortand long-term management of patients with acute coronary syndromes (ACS), with and without percutaneous coronary intervention (PCI). The thienopyridine clopidogrel is accepted as a key component of antiplatelet management and is recommended in current treatment guidelines as addon therapy to aspirin in secondary prevention to reduce coronary risk in patients with ACS and/or following PCI. The FDA Cardiovascular and Renal Drugs Advisory Committee met on February 3, 2009, and recommended approval of prasugrel, but with guidance to physicians about increased risk in low-weight or elderly patients and avoidance of use (a) around coronary artery bypass graft (CABG) or other surgical or invasive procedures and (b) in patients with prior or current stroke or transient ischemic attack (TIA).. To review the published literature examining primarily the clinical efficacy and safety of prasugrel in ACS patients.. The PubMed database was searched for English language studies involving the use of prasugrel in human subjects published up to April 2009 using the keyword "prasugrel." The review focused on randomized, controlled trials with clinical end points. Abstracts from recent scientific meetings (up to November 2008) were also searched for relevant studies, as was the FDA briefing document prepared in advance of the advisory committee meeting on February 3, 2009.. Of the 124 published papers identified, 28 pertained to research in human subjects: 21 on prasugrel pharmacology and 7 with clinical end points. In the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction (PRINCIPLE-TIMI) 44 trial, a cross-over study of laboratory-determined platelet activity, prasugrel produced significantly greater inhibition of platelet aggregation than clopidogrel after both loading dose (74.8% vs. 31.8% at 6 hours, P < 0.001) and maintenance dose (day 14: 61.3% vs. 46.1%, P < 0.001) in patients with stable coronary artery disease (CAD). In the only end point outcomes study (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction [TRITON-TIMI 38]) there was a significant reduction in adverse cardiac outcomes in patients with ACS treated with prasugrel, 94% of whom received at least 1 coronary stent. The incidence of the primary composite end point of cardiovascular death, nonfatal MI, or nonfatal stroke was 9.9% in the prasugrel group versus 12.1% in the clopidogrel group (hazard ratio = 0.81, 95% CI = 0.73-0.90, P < 0.001). However, the risk of a major bleeding event was significantly greater with prasugrel versus clopidogrel, and prasugrel appeared to be of net clinical harm in patients with a history of stroke/TIA. The FDA reviewer recommended that prasugrel use be discouraged in patients aged 75 years or older or those with a history of stroke/TIA.. Available data suggest that prasugrel offers potential as an alternative to clopidogrel with greater efficacy but with increased bleeding risk in patients with ACS who receive PCI. Data are not yet available to define the efficacy and risk-benefit profile of prasugrel in patients not undergoing PCI.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Atherosclerosis; Clopidogrel; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Randomized Controlled Trials as Topic; Risk Factors; Thiophenes; Thrombosis; Ticlopidine

Diabetic patients with acute coronary syndromes (ACSs) are at a high risk for subsequent cardiovascular events but derive, at the same time, greater benefit from evidence-based therapy than non-diabetic individuals. State-of-the-art anti-thrombotic therapy includes a triple anti-platelet combination - aspirin, clopidogrel and glycoprotein (GP) IIb/IIIa receptor inhibitors - and unfractionated heparin or enoxaparin. For low- or medium-risk individuals, a treatment based on aspirin, clopidogrel and bivalirudin is a valuable alternative. Prasugrel, a new and more potent inhibitor of the platelet P2Y(12) receptor, has to be regarded as the most promising anti-thrombotic agent for diabetic patients with ACS. This agent may replace clopidogrel - and possibly GP IIb/IIIa inhibitors - in the future. In addition to aggressive anti-thrombotic therapy, diabetic patients should undergo systematic early invasive angiography if presenting with non-ST-segment elevation ACS, and immediate percutaneous coronary intervention if presenting with ST-segment elevation myocardial infarction. Indeed, the benefit derived from these strategies appears to be more pronounced in the diabetic population than in non-diabetic individuals. Despite the benefit, multiple surveys have demonstrated that, in the setting of ACS, diabetic patients receive evidence-based therapy less frequently than non-diabetic counterparts.

Topics: Acute Coronary Syndrome; Anticoagulants; Aspirin; Blood Glucose; Clopidogrel; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Enoxaparin; Hirudins; Humans; Hypoglycemic Agents; Peptide Fragments; Piperazines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prasugrel Hydrochloride; Randomized Controlled Trials as Topic; Recombinant Proteins; Thiophenes; Thrombosis; Ticlopidine

Topics: Animals; Biotransformation; Clopidogrel; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prodrugs; Purinergic P2 Receptor Antagonists; Randomized Controlled Trials as Topic; Risk Assessment; Thiophenes; Thrombosis; Ticlopidine

Patients who present with acute coronary syndromes, particularly ST-segment elevation myocardial infarction (STEMI), have abnormalities in platelet size and function that predispose to thrombotic events. Both preprocedural platelet reactivity and mean platelet volume are directly correlated with the occurrence of adverse ischemic events and impaired microvascular reperfusion following primary percutaneous coronary intervention (PCI) for STEMI. The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial demonstrated a similar ischemic event rate to 30 days with a significantly lower bleeding event rate (enhanced net clinical benefit) in favor of bivalirudin monotherapy (with provisional platelet glycoprotein [GP] IIb/IIIa receptor blockade) in comparison with unfractionated heparin plus GP IIb/IIIa blockade in patients undergoing primary PCI for STEMI. The bivalirudin monotherapy was associated with a highly significant greater incidence of acute stent thrombosis. This observation provides the opportunity for strategies that enhance periprocedural platelet inhibition to reduce stent thrombosis and to potentially improve the safety and efficacy of periprocedural adjunctive pharmacotherapy above that achieved by bivalirudin monotherapy alone.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Chemotherapy, Adjuvant; Clopidogrel; Drug Therapy, Combination; Hemorrhage; Heparin; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Piperazines; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prasugrel Hydrochloride; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Assessment; Thiophenes; Thrombosis; Ticlopidine; Time Factors; Treatment Outcome

Prasugrel is a new P2Y(12) receptor antagonist that has been investigated for the treatment of atherothrombosis in patients with cardiovascular disease undergoing percutaneous coronary intervention (PCI). Similar to other thienopyridines, prasugrel is a prodrug that requires biologic conversion to active metabolites. Studies have demonstrated the ability of prasugrel to selectively and irreversibly inhibit ADP-induced platelet aggregation to a greater degree than clopidogrel. In a large randomized, double-blind, double-dummy clinical trial, it was demonstrated that treatment with prasugrel (n = 6813; 60 mg loading dose followed by 10 mg/day) significantly reduced the incidence of a composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke during the median follow-up of 14.5 months, compared with clopidogrel (n = 6795; 300 mg loading dose followed by 75 mg/day) in patients with acute coronary syndromes scheduled to undergo PCI. The number of patients who would need to be treated with prasugrel instead of clopidogrel in order to prevent one primary efficacy outcome was 46. Landmark analyses found that prasugrel not only reduced the incidence of individual clinical endpoints and stent thrombosis during the loading dose phase (randomization to 3 days), but also that these benefits continued throughout the maintenance phase (from 3 days until the end of the trial). Nonsurgical-related Thrombolysis In Myocardial Infarction (TIMI)-major and life-threatening bleeds were significantly more frequent in patients receiving prasugrel compared with clopidogrel. Patients with a history of stroke or transient ischemic attack (TIA) seem to be at especially high risk for bleeding, as well as patients aged >75 years and those weighing <60 kg. A prespecified analysis of net clinical benefit, which took into account the effects on both the primary efficacy and safety endpoints, was conducted. After taking into account the higher bleeding rates, the net clinical benefit still favored prasugrel use compared with clopidogrel. However, patients with prior stroke or TIA, patients older than 75 years, and patients weighing <60 kg did not demonstrate a net clinical benefit with prasugrel use. Prasugrel was approved for use in Europe by the European Commission in February 2009, and is currently available in the UK. In July 2009, the US Food and Drug Administration (FDA) approved the use of prasugrel for the reduction of thrombotic card

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Atherosclerosis; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Thiophenes; Thrombosis

Antiplatelet agents are the cornerstone of treatment for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Clopidogrel, when added to aspirin, has demonstrated considerable success at reducing thrombotic complications of ACS and/or PCI compared to aspirin alone and is standard of care for the management of patients with ACS and in patients undergoing PCI. Prasugrel is a novel thienopyridine antiplatelet agent recently approved for the treatment of patients with ACS undergoing PCI. Prasugrel provides greater and more consistent platelet inhibition than clopidogrel due to earlier and more extensive formation of its active metabolite. The enhanced platelet inhibition with prasugrel led to a reduction in major adverse cardiovascular events in patients with moderate to high risk ACS scheduled for PCI in the phase 3 TRITON-TIMI 38 trial. This benefit was seen more in patients suffering a STEMI and those with diabetes. However, this reduction in events was met with a significant increase in the risk of bleeding which overcame prasugrel's benefit in certain groups. Future studies with prasugrel are needed to determine its optimal utilization to minimize bleeding risks and evaluate its outcomes in ACS and safety profile in special patient populations.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Clopidogrel; Hemorrhage; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Risk Assessment; Thiophenes; Thrombosis; Ticlopidine; Treatment Outcome

Dual antiplatelet therapy with aspirin and clopidogrel is a cornerstone of the management of patients with acute coronary syndromes and following percutaneous coronary intervention. Despite the proven benefits, clear limitations of clopidogrel exist. Prasugrel is a third-generation thienopyridine antiplatelet agent with pharmacologic characteristics that overcome some of the limitations of clopidogrel, but at the expense of increased bleeding. The promising results seen with prasugrel in large, randomized trials led to its recent approval by the US Food and Drug Administration for reducing thrombotic cardiovascular events in patients with acute coronary syndromes managed with percutaneous coronary intervention. This article will review the limitations of standard antiplatelet therapy and discuss the clinical application of prasugrel.

Topics: Acute Coronary Syndrome; Angioplasty; Clopidogrel; Hemorrhage; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Randomized Controlled Trials as Topic; Thiophenes; Thrombosis; Ticlopidine

With the availability of new data and the recent release of new European and US guidelines, contemporary care paradigms for the treatment of patients with non-ST-elevation acute coronary syndromes (NSTE ACS), including those undergoing percutaneous coronary intervention, are likely to undergo substantial changes. In recognition of this shifting landscape as well as the impact of new guidelines on care models for the treatment of patients with NSTE ACS, a roundtable was convened on October 25, 2007, to discuss the implications of these changes. The purpose of this review is to summarize the presentations and subsequent discussions from the roundtable, which examined the guidelines and evidence from a variety of perspectives, and to explore the best ways to incorporate new treatment paradigms into everyday clinical care. The multiple viewpoints expressed by the roundtable attendees illustrate the recognition that at this point, consensus has not been reached on the optimum algorithm for treatment of these patients. This article focuses on issues discussed during the roundtable from the perspective of the practicing cardiologist.

Topics: Acute Coronary Syndrome; Algorithms; Angioplasty, Balloon, Coronary; Anticoagulants; Aspirin; Cardiovascular Agents; Clinical Trials as Topic; Clopidogrel; Emergency Treatment; Evidence-Based Medicine; Fibrinolytic Agents; Hirudins; Humans; Peptide Fragments; Piperazines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Postoperative Hemorrhage; Practice Guidelines as Topic; Prasugrel Hydrochloride; Recombinant Proteins; Risk Assessment; Stents; Thiophenes; Thrombosis; Ticlopidine

A common pathophysiological course in vascular diseases is an overwhelming activation and aggregation of blood platelets, which results in atherothrombosis. By causing the last decisive step of cerebral, coronary, or peripheral arterial ischemia thrombotic complications of atherosclerotic disease represent a major player in death cause statistics of most western countries. The development of novel therapies against platelet-dependent thrombosis and the concurrent improvement of existing therapeutic strategies thus is a paramount focus of pharmaceutical research. Currently, efficiency, dosing and indications of established antiplatelet substances are being re-evaluated, whilst new, so far unrecognized molecular targets for inhibition of platelet activity come up front. This not only allows for interesting new therapeutical options, but also widens our insight into the role platelets play in atherosclerosis in general. This article summarizes the relevant pathophysiology of platelet activation, presents current concepts in antiplatelet drug therapy, and highlights the role of platelets in vascular diseases apart from atherothrombosis.

Topics: Atherosclerosis; Clopidogrel; Drug-Eluting Stents; Humans; Piperazines; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Pyridines; Receptors, Thromboxane; Signal Transduction; Thiophenes; Thrombosis; Ticlopidine

Platelet activation and aggregation play key roles in the management of ischemic complications of acute coronary syndromes and percutaneous coronary intervention. Dual antiplatelet therapy with aspirin and the thienopyridine clopidogrel has become the standard of care for prevention of such complications. Prasugrel, a novel thienopyridine antiplatelet agent, has been demonstrated to have favorable pharmacologic properties, including rapid onset and potent and consistent inhibition of platelet aggregation. When compared directly against clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38), prasugrel resulted in significant reductions in ischemic events including myocardial infarction and stent thrombosis, but with more bleeding.

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

Atherothrombosis is an acute complication that develops on the surface of a ruptured atheromatous plaque or as a consequence of endothelial erosion that may cause myocardial infarction or ischemic stroke. Anti-platelet therapy has been highly effective at reducing atherothrombotic risk. However, patients continue to experience thrombotic events despite the use of agents such as aspirin and clopidogrel. Many of these events occur, in part, because of the inadequate response to these drugs. This has prompted the pursuit of novel agents with aspirations of optimizing anti-platelet therapy. New opportunities have emerged to address the deficiencies in current anti-platelet agents. Among these are thrombin receptor antagonists, such as SCH530348 and P2Y12 receptor antagonists, such as prasugrel, cangrelor, and AZD6140. The patents describe these novel compounds and compositions, their ability to inhibit platelet activation and/or aggregation and their use in the treatment of atherothrombotic diseases. These drugs have pharmacologic properties that translate into increased potency, more rapid onset of action, and less variability in response compared to standard therapy. In this review, we highlight the current data on these potential drugs and the role they could play in atherothrombotic disease.

Topics: Adenosine Monophosphate; Animals; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Receptors, Thrombin; Thiophenes; Thrombosis

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

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

CS-747 (prasugrel, LY640315) is a member of the thienopyridine class of oral platelet aggregation inhibitors that includes ticlopidine and clopidogrel. A single oral administration of CS-747 produced a dose-related inhibition of platelet aggregation in rats that was approximately 10- and 100-fold more potent than that of clopidogrel and ticlopidine, respectively. The antiaggregatory effect of CS-747 was evident at 30 minutes and lasted until 72 hours after dosing, indicating fast onset and long duration of action. CS-747 showed more potent antithrombotic activity compared with clopidogrel and ticlopidine with the same rank order as the antiaggregatory potencies. Combined administration of CS-747 with aspirin to rats produced substantially greater inhibition of both platelet aggregation and thrombus formation compared with each agent alone. The antiplatelet action of CS-747 is due to irreversible and selective blockade of platelet P2Y (12) adenosine diphosphate (ADP) receptors by its active metabolite R-138727. In phase I studies, a single oral dose of CS-747 (30 and 75 mg) produced > 50% inhibition of ADP-induced platelet aggregation, with rapid onset (1 hour) and long duration (> 48 hours) of action. In healthy volunteers, once-daily administration of 10 mg CS-747 for 10 days showed significant cumulative inhibition of platelet aggregation from 2 days after the first dose until at least 2 days after the final dose. Studies conducted to date indicate that CS-747 is a highly effective antiplatelet and antithrombotic agent and is anticipated to be effective in the treatment of atherothrombotic and other ischemic vascular diseases.

Topics: Adenosine Diphosphate; Adult; Animals; Aspirin; Biotransformation; Clinical Trials, Phase I as Topic; Clopidogrel; Collagen; Drug Evaluation, Preclinical; Drug Synergism; Fibrinolytic Agents; Hemostasis; Humans; Male; Membrane Proteins; Molecular Structure; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prodrugs; Purinergic P2 Receptor Antagonists; Pyridines; Rats; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Thiophenes; Thrombin; Thrombosis; Ticlopidine

Despite increased atherothrombotic risk in type 2 diabetes mellitus, (T2DM) the best preventative antithrombotic strategy remains undetermined. We defined the effects of three antiplatelet agents on functional readout and biomarker kinetics in platelet activation and coagulation in patients with T2DM.. 56 patients with T2DM were randomised to antiplatelet monotherapy with aspirin 75 mg once daily (OD), clopidogrel 75 mg OD or prasugrel 10 mg OD during three periods of a crossover study. Platelet aggregation (PA) was determined by light-transmittance aggregometry and P-selectin expression by flow cytometry. Markers of fibrin clot dynamics, inflammation and coagulation were measured. Plasma levels of 14 miRNA were assessed by quantitative polymerase chain reactions.. Of the 56 patients, 24 (43%) were receiving aspirin for primary prevention of ischaemic events and 32 (57%) for secondary prevention. Prasugrel was the strongest inhibitor of ADP-induced PA (mean ± SD maximum response to 20μmol/L ADP 77.6 ± 8.4% [aspirin] vs. 57.7 ± 17.6% [clopidogrel] vs. 34.1 ± 14.1% [prasugrel], p < 0.001), P-selectin expression (30 μmol/L ADP; 45.1 ± 21.4% vs. 27.1 ± 19.0% vs. 14.1 ± 14.9%, p < 0.001) and collagen-induced PA (2 μg/mL; 62.1 ± 19.4% vs. 72.3 ± 18.2% vs. 60.2 ± 18.5%, p < 0.001). Fibrin clot dynamics and levels of coagulation and inflammatory proteins were similar. Lower levels of miR-24 (p = 0.004), miR-191 (p = 0.019), miR-197 (p = 0.009) and miR-223 (p = 0.014) were demonstrated during prasugrel-therapy vs. aspirin. Circulating miR-197 was lower in those cardiovascular disease during therapy with aspirin (p = 0.039) or prasugrel (p = 0.0083).. Prasugrel monotherapy in T2DM provided potent platelet inhibition and reduced levels of a number of platelet-associated miRNAs. miR-197 is a potential marker of cardiovascular disease in this population. Clinical outcome studies investigating prasugrel monotherapy are warranted in individuals with T2DM. Trial registration EudraCT, 2009-011907-22. Registered 15 March 2010, https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-011907-22/GB.

Topics: Aged; Aspirin; Biomarkers; Blood Coagulation; Clopidogrel; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Fibrin; Humans; Male; MicroRNAs; Middle Aged; P-Selectin; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Primary Prevention; Secondary Prevention; Thrombosis; Time Factors; Treatment Outcome

To test whether administration of prasugrel after coronary artery bypass grafting (CABG) reduces saphenous vein graft (SVG) thrombosis. Use of aspirin after CABG improves graft patency, but administration of other antiplatelet agents has yielded equivocal results.. We performed a double-blind trial randomizing patients to prasugrel or placebo after CABG at four United States centers. Almost all patients were receiving aspirin. Follow-up angiography, optical coherence tomography (OCT), intravascular ultrasound (IVUS), and near-infrared spectroscopy (NIRS) were performed at 12 months. The primary efficacy endpoint was prevalence of OCT-detected SVG thrombus. The primary safety endpoint was incidence of Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) severe bleeding.. The study was stopped early due to slow enrollment after randomizing 84 patients. Mean age was 64 ± 6 years; 98% of the patients were men. Follow-up angiography was performed in 59 patients. IVUS was performed in 52 patients, OCT in 53 patients, and NIRS in 33 patients. Thrombus was identified by OCT in 56% vs 50% of patients in the prasugrel vs placebo groups, respectively (P=.78). Angiographic SVG failure occurred in 24% of patients in the prasugrel arm vs 40% in the placebo arm (P=.19). The 1-year incidence of major adverse cardiovascular events was 14.3% vs 2.4% in the prasugrel and placebo groups, respectively (P=.20), without significant differences in GUSTO severe bleeding (P=.32).. Early SVG failure occurred in approximately one-third of patients. Prasugrel did not decrease prevalence of SVG thrombus 12 months after CABG.

Topics: Aged; Coronary Angiography; Coronary Artery Bypass; Female; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Prasugrel Hydrochloride; Saphenous Vein; Thrombosis; Treatment Outcome; Vascular Patency

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

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

To investigate the safety and efficacy of an early platelet function testing (PFT)-guided de-escalation of dual antiplatelet treatment (DAPT) in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) with bioresorbable vascular scaffolds (BVS). Early DAPT de-escalation is a new non-inferior alternative to 12-months DAPT in patients with biomarker positive ACS treated with stent implantation. In this post-hoc analysis of the TROPICAL-ACS trial, which randomized 2610 ACS patients to a PFT-guided DAPT de-escalation (switch from prasugrel to clopidogrel) or to control group (uniform prasugrel), we compared clinical outcomes of patients (n = 151) who received a BVS during the index PCI. The frequency of the primary endpoint (cardiovascular death, myocardial infarction, stroke or BARC ≥ 2 bleeding) was 8.8% (n = 6) in the de-escalation group vs. 12.0% (n = 10) in the control group (HR 0.72, 95% CI 0.26-1.98, p = 0.52) at 12 months. One early definite stent thrombosis (ST) occurred in the control group (day 19) and 1 possible ST (sudden cardiovascular death) in the de-escalation group (day 86), both despite prasugrel treatment and in a background of high on-treatment platelet reactivity assessed at day 14 after randomization (ADP-induced platelet aggregation values of 108 U and 59 U, respectively). A PFT-guided DAPT de-escalation strategy could potentially be a safe and effective strategy in ACS patients with BVS implantation but the level of platelet inhibition may be of particular importance. This hypothesis-generating post-hoc analysis requires verification in larger studies with upcoming BVS platforms.

Topics: Absorbable Implants; Acute Coronary Syndrome; Adolescent; Adult; Aged; Aged, 80 and over; Blood Vessel Prosthesis Implantation; Clopidogrel; Drug Substitution; Female; Hemorrhage; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Thrombosis; Tissue Scaffolds; Young Adult

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

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

Previous studies have suggested that peri-procedural myocardial infarction (PMI) following percutaneous coronary intervention (PCI) is associated with adverse short- and long-term outcomes, and several morphological predictors of PMI have been studied. However, the determinants of PMI under novel anti-platelet therapy are not fully elucidated.. PRASFIT-Elective is a multicenter, parallel-group study of PCI patients in non-acute settings receiving either prasugrel or clopidogrel in addition to aspirin. Among 742 study patients, 94 (116 lesions) underwent optical coherence tomography (OCT) to evaluate the area of intra-stent tissue (IST, which comprises tissue protrusion and thrombus) after stenting in addition to standard parameters. We investigated the relationship between the peak creatine kinase (CK)-MB fraction levels after PCI and post-stent OCT findings, as well as on-treatment platelet reactivity determined by the P2Y. Following elective PCI, a large IST area originating from a lipid-rich plaque and a smaller minimal stent diameter were associated with PMI.

Topics: Aged; Aspirin; Clopidogrel; Creatine Kinase, MB Form; Double-Blind Method; Elective Surgical Procedures; Female; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Stents; Thrombosis; Ticlopidine; Tomography, Optical Coherence

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

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

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

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

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

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

There are very few clinical data concerning the safety of switching from clopidogrel to prasugrel in patients undergoing coronary stenting. However, in the daily activity, clinicians face the decision of switching patients at high-risk of thrombotic events from clopidogrel to prasugrel. Thus, we sought to evaluate clinical events in patients undergoing coronary stent implantation and prasugrel therapy with (SWITCH group) or without (NAÏVE group) prior clopidogrel therapy. A total of 454 patients with stable or unstable coronary artery disease, aged 70 ± 10 years, underwent non-emergent stent implantation and received prasugrel therapy. Of these, 315 (69 %) patients received clopidogrel before switching to prasugrel therapy. In 239 patients with high residual platelet reactivity (HRPR) on clopidogrel, prasugrel decreased platelet aggregation from 72 ± 11 to 43 ± 16 % (p < 0.001). There was no difference in in-hospital major or minor TIMI bleeding (2.8 vs. 4.3 %; p = 0.411) between the SWITCH and NAÏVE groups as well as in mortality, acute stent thrombosis, reinfarction and stroke rates. At multivariable analysis, independent predictors of bleeding were female gender (OR 5.56 [1.41-19.88] p = 0.014) and chronic renal failure (OR 6.27 [1.59-21.65] p = 0.009), but switching therapy did not. This result was confirmed after switching propensity score adjustment (c-statistic 0.81; Hosmer-Lemeshow test p = 860). Switching from clopidogrel to prasugrel in patients undergoing non-emergent coronary stent implantation seems to be tolerated with no overt signs of increased bleeding.

Topics: Aged; Aged, 80 and over; Clopidogrel; Coronary Artery Disease; Drug Substitution; Female; Hemorrhage; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Piperazines; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Renal Insufficiency, Chronic; Sex Factors; Stents; Thiophenes; Thrombosis; Ticlopidine

Dual antiplatelet therapy is recommended after coronary stenting to prevent thrombotic complications, yet the benefits and risks of treatment beyond 1 year are uncertain.. Patients were enrolled after they had undergone a coronary stent procedure in which a drug-eluting stent was placed. After 12 months of treatment with a thienopyridine drug (clopidogrel or prasugrel) and aspirin, patients were randomly assigned to continue receiving thienopyridine treatment or to receive placebo for another 18 months; all patients continued receiving aspirin. The coprimary efficacy end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events (a composite of death, myocardial infarction, or stroke) during the period from 12 to 30 months. The primary safety end point was moderate or severe bleeding.. A total of 9961 patients were randomly assigned to continue thienopyridine treatment or to receive placebo. Continued treatment with thienopyridine, as compared with placebo, reduced the rates of stent thrombosis (0.4% vs. 1.4%; hazard ratio, 0.29 [95% confidence interval {CI}, 0.17 to 0.48]; P<0.001) and major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%; hazard ratio, 0.71 [95% CI, 0.59 to 0.85]; P<0.001). The rate of myocardial infarction was lower with thienopyridine treatment than with placebo (2.1% vs. 4.1%; hazard ratio, 0.47; P<0.001). The rate of death from any cause was 2.0% in the group that continued thienopyridine therapy and 1.5% in the placebo group (hazard ratio, 1.36 [95% CI, 1.00 to 1.85]; P=0.05). The rate of moderate or severe bleeding was increased with continued thienopyridine treatment (2.5% vs. 1.6%, P=0.001). An elevated risk of stent thrombosis and myocardial infarction was observed in both groups during the 3 months after discontinuation of thienopyridine treatment.. Dual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding. (Funded by a consortium of eight device and drug manufacturers and others; DAPT ClinicalTrials.gov number, NCT00977938.).

Topics: Aged; Aspirin; Clopidogrel; Drug Administration Schedule; Drug Therapy, Combination; Drug-Eluting Stents; Female; Hemorrhage; Humans; Incidence; Male; Middle Aged; Myocardial Ischemia; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes; Thrombosis; Ticlopidine; Time Factors

The well-described morning peak in the onset of acute coronary syndromes has been partly attributed to increased platelet activity upon arising. It has been suggested that stent thrombosis (ST) exhibits a similar pattern. We assessed whether a diurnal variation in ST occurs, and whether more robust antiplatelet therapy with prasugrel (vs clopidogrel) can attenuate a morning excess.. Patients from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial (N = 13 608) with adjudicated ST classified per the Academic Research Consortium definitions of definite (N = 135) and probable (N = 27) were grouped into prespecified 8-hour intervals by time of onset: early (6 am-2 pm), late-day (2 pm-10 pm), and overnight (10 pm-6 am). We compared the rates per 1000 patients of ST across time intervals and stratified by treatment and stent type.. A diurnal variation in definite/probable ST was observed with rates of 6.5, 3.7, and 2.1 for early, late-day, and overnight intervals, respectively (P < .001), per 1000 patients treated. A sensitivity analysis excluding periprocedural acute-ST (<24 hours after index percutaneous coronary intervention [PCI]) resulted in similar findings (5.2, 2.5, and 1.8 per 1000, P < .001). The circadian variation in ST was observed in patients on clopidogrel (9.7, 4.8, and 3.1 per 1000, P < .001) with the highest rate of ST early in the day. Patients on prasugrel also demonstrated a circadian variation with particularly low rates of overnight ST (3.4, 3.0, and 1.1 per 1000, P = .020).. In TRITON-TIMI 38 trial, the timing of ST exhibited a significant diurnal variation similar to that seen with onset of other acute coronary syndromes. ST occurred less frequently among patients randomized to prasugrel compared to clopidogrel with the greatest absolute reduction (6.2 per 1000 patients) in events earlier in the day when platelet activity is known to be highest.

Topics: Acute Coronary Syndrome; Aged; Circadian Rhythm; Clopidogrel; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Stents; Thiophenes; Thrombosis; Ticlopidine; Time Factors; Treatment Outcome

In TRITON-TIMI 38, levels of the prasugrel active metabolite (pras-AM) were measured in a population pharmacokinetic substudy that characterized the intrinsic and extrinsic factors influencing exposure. Higher exposure to the pras-AM was observed in low-weight or very elderly patients. The authors hypothesized that this higher exposure might explain the higher risk of non-coronary artery bypass graft (CABG)-related TIMI-related bleeding observed in these 2 patient populations. The relationship between estimated exposure to the pras-AM and clinical outcomes was assessed in 1159 prasugrel-treated patients enrolled in the substudy using multivariable logistic regression analysis. There was no relationship between pras-AM exposure and efficacy through 3 days or after 3 days. Higher estimated pras-AM exposure was associated with a higher incidence of non-CABG-related TIMI major or minor bleeding after 3 days (P < .05) but not through 3 days from start of study drug. Factors associated with increased risk for non-CABG-related TIMI bleeding (≥75 years and <60 kg) also identified subgroups with higher exposure to the pras-AM. Within low body weight and very elderly subgroups, bleeding was largely confined to patients having the highest exposure to the pras-AM, indicating that a prasugrel lower dose in these subgroups may reduce the risk of bleeding while maintaining efficacy.

Topics: Acute Coronary Syndrome; Age Factors; Aged; Biotransformation; Body Weight; Dose-Response Relationship, Drug; Double-Blind Method; Hemorrhage; Humans; Incidence; Male; Models, Biological; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prodrugs; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Severity of Illness Index; Thiophenes; Thrombosis

The salt linked to the clopidogrel molecule in generic preparations is suspected to affect its clinical efficacy. There is a lack of information about inhibition of platelet reactivity by generic preparations.. To compare the effect of original clopidogrel (clopidogrel bisulphate [Plavix(®)]), generic clopidogrel preparations (clopidogrel hydrochloride [Clopidogrel-Mepha(®)]; clopidogrel besylate [Clopidogrel Sandoz(®)]) and prasugrel (Efient(®)) on platelet reactivity in patients with coronary artery disease.. Patients with coronary artery disease treated with stents received, in a random sequence, original clopidogrel bisulphate, clopidogrel hydrochloride and clopidogrel besylate. Platelet function was assessed with the Multiplate analyser after an initial loading dose (600 mg) and at day 10 after each treatment period. Prasugrel was given for another 10 days. An adenosine diphosphate (ADP) test value<46 antiaggregation units (U) was defined as therapeutic platelet inhibition.. Sixty patients (mean age 69 ± 10 years; 50 men) were randomized. Original clopidogrel bisulphate, clopidogrel hydrochloride and clopidogrel besylate provided similar inhibition of platelet reactivity with values of 31 ± 25, 33 ± 28 and 28 ± 23 U, respectively (P not significant). Prasugrel provided better inhibition of platelet function (10 ± 11 vs. 31 ± 25 U for clopidogrel bisulphate; P<0.001). An ADP test value>46 U was measured in 11 patients (18%) with clopidogrel bisulphate, 13 (22%) with clopidogrel besylate and 13 (22%) with clopidogrel hydrochloride compared with only one (2%) with prasugrel.. Generic clopidogrel preparations provided similar inhibition of platelet reactivity to original clopidogrel bisulphate, although prasugrel was more efficient.

Topics: Adenosine Diphosphate; Aged; Aged, 80 and over; Clopidogrel; Cross-Over Studies; Drugs, Generic; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Patient Selection; Percutaneous Coronary Intervention; Piperazines; Platelet Activation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Single-Blind Method; Stents; Therapeutic Equivalency; Thiophenes; Thrombosis; Ticlopidine; Treatment Outcome

Intracoronary stenting can improve procedural success and reduce restenosis compared with balloon angioplasty in patients with acute coronary syndromes, but can also increase the rate of thrombotic complications including stent thrombosis. The TRITON-TIMI 38 trial has shown that prasugrel-a novel, potent thienopyridine-can reduce ischaemic events compared with standard clopidogrel therapy. We assessed the rate, outcomes, and prevention of ischaemic events in patients treated with prasugrel or clopidogrel with stents in the TRITON-TIMI 38 study.. Patients with moderate-risk to high-risk acute coronary syndromes were included in our analysis if they had received at least one coronary stent at the time of the index procedure following randomisation in TRITON-TIMI 38, and were further subdivided by type of stent received. Patients were randomly assigned in a 1 to 1 fashion to receive a loading dose of study drug (prasugrel 60 mg or clopidogrel 300 mg) as soon as possible after randomisation, followed by daily maintenance therapy (prasugrel 10 mg or clopidogrel 75 mg). All patients were to receive aspirin therapy. Treatment was to be continued for a minimum of 6 months and a maximum of 15 months. Randomisation was not stratified by stents used or stent type. The primary endpoint was the composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Stent thrombosis was assessed using Academic Research Consortium definitions, and analysis was by intention to treat. TRITON-TIMI 38 is registered with ClinicalTrials.gov, number NCT00097591.. 12,844 patients received at least one coronary stent; 5743 received only drug-eluting stents, and 6461 received only bare-metal stents. Prasugrel compared with clopidogrel reduced the primary endpoint (9.7 vs 11.9%, HR 0.81, p=0.0001) in the stented cohort, in patients with only drug-eluting stents (9.0 vs 11.1%, HR 0.82, p=0.019), and in patients with only bare-metal stents (10.0 vs 12.2%, HR 0.80, p=0.003). Stent thrombosis was associated with death or myocardial infarction in 89% (186/210) of patients. Stent thrombosis was reduced with prasugrel overall (1.13 vs 2.35%, HR 0.48, p<0.0001), in patients with drug-eluting stents only (0.84 vs 2.31%, HR 0.36, p<0.0001), and in those with bare-metal stents only (1.27 vs 2.41%, HR 0.52, p=0.0009).. Intensive antiplatelet therapy with prasugrel resulted in fewer ischaemic outcomes including stent thrombosis than with standard clopidogrel. These findings were statistically robust irrespective of stent type, and the data affirm the importance of intensive platelet inhibition in patients with intracoronary stents.

Topics: Acute Coronary Syndrome; Administration, Oral; Aged; Angioplasty, Balloon, Coronary; Clopidogrel; Female; Humans; Male; Middle Aged; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Stents; Thiophenes; Thrombosis; Ticlopidine; Treatment Outcome

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Clopidogrel; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes; Thrombosis; Ticlopidine

Topics: Clopidogrel; Coronary Disease; Humans; Membrane Proteins; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Stents; Thiophenes; Thrombosis; Ticlopidine

Dual-antiplatelet therapy with aspirin and a thienopyridine is a cornerstone of treatment to prevent thrombotic complications of acute coronary syndromes and percutaneous coronary intervention.. To compare prasugrel, a new thienopyridine, with clopidogrel, we randomly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding.. The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). We also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P=0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P=0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P=0.23) and fatal bleeding (0.4% vs. 0.1%; P=0.002).. In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. (ClinicalTrials.gov number, NCT00097591 [ClinicalTrials.gov].)

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Aspirin; Clopidogrel; Double-Blind Method; Drug Therapy, Combination; Female; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prodrugs; Purinergic P2 Receptor Antagonists; Stroke; Thiophenes; Thrombosis; Ticlopidine

Dual antiplatelet therapy with aspirin and clopidogrel is standard for prevention of thrombotic complications of percutaneous coronary intervention (PCI). Prasugrel is a thienopyridine that is more potent, more rapid in onset, and more consistent in inhibition of platelets than clopidogrel. TRITON-TIMI 38 is designed to compare prasugrel with clopidogrel in moderate to high-risk patients with acute coronary syndrome (ACS).. TRITON-TIMI 38 is a phase 3, randomized, double-blind, parallel-group, multinational, clinical trial. Approximately 13,000 patients with moderate to high-risk ACS undergoing PCI (9500 unstable angina/non-ST-segment elevation myocardial infarction [MI], 3500 ST-segment elevation MI) will be randomized to prasugrel 60 mg loading dose followed by 10 mg daily or clopidogrel 300 mg loading dose followed by 75 mg daily for up to 15 months. The primary end point is the time of the first event of cardiovascular death, MI, or stroke. Analyses will be performed first in the unstable angina/non-ST-segment elevation MI cohort and, conditionally, on the whole ACS population. Major safety end points include TIMI major and minor bleeding unrelated to coronary artery bypass graft surgery.. TRITON-TIMI 38 is a phase 3 comparison of prasugrel versus clopidogrel in patients with moderate to high-risk ACS undergoing PCI. In addition, it is the first large-scale clinical events trial to assess whether a thienopyridine regimen that achieves a higher level of inhibition of platelet aggregation than the standard therapy results in an improvement in clinical outcomes.

Topics: Acute Disease; Aged; Angioplasty, Balloon, Coronary; Clopidogrel; Coronary Disease; Dose-Response Relationship, Drug; Double-Blind Method; Follow-Up Studies; Humans; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Research Design; Syndrome; Thiophenes; Thrombolytic Therapy; Thrombosis; Ticlopidine; Treatment Outcome

Pharmacological inhibition of the platelet ADP-receptor P2Y

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

Based on recent clinical data, the 2020 ESC guidelines on non-ST-elevation acute coronary syndrome (NSTE-ACS) suggest to tailor antithrombotic strategy on individual thrombotic risk. Nonetheless, prevalence and prognostic impact of the high thrombotic risk (HTR) criteria proposed are yet to be described. In this analysis from the PROMETHEUS registry, we assessed prevalence and prognostic impact of HTR, defined according to the 2020 ESC NSTE-ACS guidelines, and if the benefits associated with prasugrel vs. clopidogrel vary with thrombotic risk.. PROMETHEUS was a multicentre prospective study comparing prasugrel vs. clopidogrel in ACS patients undergoing percutaneous coronary intervention (PCI). Patients were at HTR if presenting with one clinical plus one procedural risk feature. The primary endpoint was major adverse cardiac events (MACE), composite of death, myocardial infarction, stroke, or unplanned revascularization, at 1 year. Adjusted hazard ratio (adjHR) and 95% confidence intervals (CIs) were calculated with propensity score stratification and multivariable Cox regression. Among 16 065 patients, 4293 (26.7%) were at HTR and 11 772 (73.3%) at low-to-moderate thrombotic risk. The HTR conferred increased incidence of MACE (23.3 vs. 13.6%, HR 1.85, 95% CI 1.71-2.00, P < 0.001) and its single components. Prasugrel was prescribed in patients with less comorbidities and risk factors and was associated with reduced risk of MACE (HTR: adjHR 0.83, 95% CI 0.68-1.02; low-to-moderate risk: adjHR 0.75, 95% CI 0.64-0.88; pinteraction = 0.32).. High thrombotic risk, as defined by the 2020 ESC NSTE-ACS guidelines, is highly prevalent among ACS patients undergoing PCI. The HTR definition had a strong prognostic impact, as it successfully identified patients at increased 1 year risk of ischaemic events.

Topics: Acute Coronary Syndrome; Clopidogrel; Humans; Patient Discharge; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prospective Studies; Thrombosis; Treatment Outcome

Intracoronary thrombus formation is a main cause of acute myocardial infarction triggered by platelet activation. However, there are no data on the impact of different treatment strategies with antiplatelet agents before percutaneous coronary intervention (PCI) on histological characteristics of thrombus formation.. In this study, we investigate the impact of preinterventional administration of the P2Y12-inhibitors clopidogrel and prasugrel on thrombus composition, highlighting significant changes associated with the antiplatelet pre-treatment.. We prospectively enrolled 104 consecutive patients with ST-segment elevation myocardial infarction (STEMI) undergoing immediate PCI and thrombus aspiration by immunohistochemical staining along with RNA-sequencing employing Nanostring analysis. Fifty-two patients were treated with either prasugrel loading (60 mg) or clopidogrel loading (600 mg) prior to PCI, respectively.. In Patients with STEMI, intracoronary thrombus architecture was significantly altered between patients pre-treated with prasugrel when compared to clopidogrel. Fibrin content of thrombi was significantly decreased (41.8 % versus 66.7 %, p = 0.009) after pre-treatment with prasugrel compared to clopidogrel. Furthermore, levels of MPO positive cells in intracoronary thrombi were significantly decreased in patients with prasugrel pre-treatment (90.5 versus 201.1, p = 0.014) indicating an association of antiplatelet pre-treatment and the inflammatory responses during thrombus formation. Most strikingly, we observed significant differences among both pre-treatment groups regarding altered RNA expression and signaling pathways of thrombo-inflammatory processes within the thrombotic material, which were independently associated with antiplatelet strategies.. Our study elucidates the impact of antiplatelet pre-treatment on thrombus remodeling and architecture, thereby lowering the risk of recurrent adverse cardiovascular events in prasugrel-treated patients.

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

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

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

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

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

To assess the impact of continued perioperative anticoagulant drug administration on bleeding and complications in patients undergoing robot-assisted radical prostatectomy.. Between January 2014 and January 2020, 620 patients with prostate cancer underwent robot-assisted radical prostatectomies and were retrospectively reviewed. Fourteen patients who discontinued antithrombotic therapy were excluded. Among the 606 included patients, 31 continued anticoagulant therapy during the perioperative phase (anticoagulant group). The anticoagulant group outcomes were compared with those of patients who continued clopidogrel and prasugrel (thienopyridine group = 13), aspirin monotherapy (aspirin group = 61), and no chronic antithrombotic agent (control group = 501). The primary outcome was the incidence of bleeding complications requiring transfusion, additional intervention, or readmission. Secondary outcomes were the incidence of thrombotic complications, estimated blood loss, and overall complication rates.. Among the 31 patients in the anticoagulant group, 20 (65%) used directed oral anticoagulants, 11 (35%) used warfarin, and 5 used combined aspirin. Only 1 (3%) patient in the anticoagulant group required postoperative transfusion, and none required additional interventions or readmission. No significant differences were detected between the anticoagulant and other groups (anticoagulant vs thienopyridine, aspirin, and control groups) regarding bleeding complications (3% vs 8%, P = .51; 0%, P = .34; 0.4%, P = .17, respectively), thrombotic complications (3% vs 0%, P = .70; 2%, P = .56; 0.2%, P = .11, respectively), estimated blood loss (200 vs 100 mL, P = .63; 175 mL, P = .64; 165 mL, P = .74, respectively), or other high-grade complications (6% vs 0%, P = .49; 2%, P = .26; 3%, P = .24, respectively).. Perioperative continuation of anticoagulant use is feasible for patients undergoing robot-assisted radical prostatectomy.

Topics: Aged; Anticoagulants; Antithrombins; Aspirin; Blood Transfusion; Clopidogrel; Continuity of Patient Care; Humans; Incidence; Male; Perioperative Care; Platelet Aggregation Inhibitors; Postoperative Hemorrhage; Prasugrel Hydrochloride; Prostatectomy; Prostatic Neoplasms; Retrospective Studies; Robotic Surgical Procedures; Thrombosis; Warfarin

The impact of antiplatelet drug effects on mid-term local arterial responses following percutaneous coronary intervention (PCI) remains uncertain. We evaluated the impact of the platelet reactivity of prasugrel on mid-term vascular healing between acute coronary syndrome (ACS) and stable coronary artery disease (CAD).Methods and Results:We conducted a prospective, 12-center study in 125 patients with ACS and 126 patients with stable CAD who underwent PCI with an everolimus-eluting stent (EES) and received dual antiplatelet therapy (DAPT) with prasugrel and aspirin. Serial optical coherence tomography (OCT) was performed immediately after PCI and at the 9-month follow-up to assess the association of P2Y. In patients undergoing EES implantation and receiving prasugrel, achieving an adequate antiplatelet effect at the time of stent implantation may regulate thrombus formation throughout the follow-up period.

Topics: Acute Coronary Syndrome; Coronary Artery Disease; Drug-Eluting Stents; Everolimus; Fibrinolytic Agents; Humans; Percutaneous Coronary Intervention; Prasugrel Hydrochloride; Prospective Studies; Thrombosis; Tomography, Optical Coherence; Treatment Outcome

Blood platelets' adenosine receptors (AR) are considered to be a new target for the anti-platelet therapy. This idea is based on in vitro studies which show that signaling mediated by these receptors leads to a decreased platelet response to activating stimuli. In vivo evidence for the antithrombotic activity of AR agonists published to date were limited, however, to the usage of relatively high doses given in bolus. The present study was aimed at verifying if these substances used in lower doses in combination with inhibitors of P2Y

Topics: Adenosine Monophosphate; Adenosine-5'-(N-ethylcarboxamide); Adult; Animals; Antithrombins; Blood Pressure; Blood-Brain Barrier; Chlorides; Diastole; Female; Ferric Compounds; Fibrinogen; Humans; Laser-Doppler Flowmetry; Male; Mice, Inbred C57BL; Permeability; Platelet Activation; Platelet Aggregation; Prasugrel Hydrochloride; Purinergic P1 Receptor Agonists; Purinergic P2Y Receptor Antagonists; Systole; Thrombosis

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

Drugs inhibiting the platelet P2Y. In this study, the pharmacodynamics of a new P2Y. CN-218 had an antiaggregatory efficacy that was at least five times more potent than that of clopidogrel but not as potent as that of prasugrel. It had a significant impact on activated partial thromboplastin time (APTT), whereby the APTT of CN-218-treated rats was approximately 9 s longer than that of the vehicle- or clopidogrel-treated group, while it had no impact on prothrombin time (PT) in rats. CN-218 had a similar potent antithrombotic effect to that of prasugrel and clopidogrel and also reduced the risk of bleeding compared to prasugrel.. CN-218 may be a promising antithrombotic agent, with potent antiplatelet and significant anticoagulant activity, as well as a lower risk of bleeding compared to clopidogrel and prasugrel.

Topics: Animals; Blood Coagulation; Blood Platelets; Carrageenan; Clopidogrel; Cyclic AMP; Disease Models, Animal; Fibrinolytic Agents; Hemorrhage; Male; Mice; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Rats, Wistar; Receptors, Purinergic P2Y12; Thiophenes; Thrombosis

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

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

The risks of bleeding and cardiovascular events in high bleeding risk (HBR) Japanese patients undergoing percutaneous coronary intervention (PCI) while receiving single-antiplatelet therapy (SAPT) remains unknown. We aimed to evaluate the frequency of bleeding and cardiovascular events associated with prasugrel monotherapy after short-term dual-antiplatelet therapy (DAPT) in Japanese HBR patients after PCI.Methods and Results:The PENDULUM mono study was a multicenter, non-interventional, prospective registry (n=1,173). The primary endpoint was the cumulative incidence of clinically relevant bleeding (CRB; Bleeding Academic Research Consortium types 2, 3, and 5) from 1 to 12 months after PCI. Secondary endpoints included major adverse cardiac and cerebrovascular events (MACCE). The proportion of patients who received prasugrel monotherapy at 12 months after PCI was 79.7%, and no cases of stent thrombosis were observed among these patients. The cumulative incidence of CRB was 3.2% from 1 to 12 months after PCI; that of MACCE was 3.8%. Severe anemia, chronic kidney disease, oral anticoagulant use at discharge, and heart failure were significantly associated with CRB.. Among HBR patients undergoing PCI who were not suitable for concomitant aspirin and were scheduled for prasugrel monotherapy, most patients were on prasugrel monotherapy after DAPT. Cumulative incidences of CRB and MACCE after periprocedural period were 3.2% and 3.8%, respectively, and no cases of stent thrombosis were reported. SAPT might be a suitable alternative to DAPT.

Topics: Hemorrhage; Humans; Japan; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prospective Studies; Thrombosis; Treatment Outcome

Large inter-individual variation in platelet response to endogenous agonists and pharmacological agents, including resistance to antiplatelet therapy, prompts a search for novel platelet inhibitors and development new antithrombotic strategies. The present in vitro study evaluates the beneficial effects of three adenosine receptor (AR) agonists (regadenoson, LUF 5835 and NECA), different in terms of their selectivity for platelet adenosine receptors, when used alone and in combination with P2Y

Topics: Adenosine Monophosphate; Drug Resistance; Female; Humans; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P1 Receptor Agonists; Receptors, Purinergic P2Y12; Thrombosis

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

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

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

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

The impact of dual antiplatelet therapy (DAPT) with adjusted-dose (3.75 mg/day) prasugrel for Japanese patients has not been fully investigated in terms of local arterial healing following the elective percutaneous coronary intervention (PCI). The ROUTE-01 elective study was a prospective, 12-center and single-arm registry that enrolled 123 patients who underwent elective PCI with everolimus-eluting stents (EESs) under DAPT with a combination of adjusted-dose prasugrel and aspirin. Serial optical coherence tomography (OCT) was performed at the index PCI and 9-month follow-up to assess the relationship between in-stent thorombus (IST) and residual platelet reactivity measuring platelet reactivity unit (PRU). The patients were classified as extensive, intermediate, and poor metabolizers by cytochrome P450 2C19 (CYP2C19) loss-of-function polymorphisms. The prevalence of IST was 9.0% by 9-month OCT, with no difference amongst the three groups (p = 0.886). The incidences of malapposed and uncovered struts were not different among the groups. PRU was not statistically different among the groups. In multivariate logistic regression analysis, the independent predictor for IST on 9-month OCT was irregular protrusion (odds ratio = 8.952, p = 0.037) on post-PCI OCT, not CYP2C19 loss-of-function polymorphisms. An adequate anti-thrombotic effect with an acceptable incidence of IST was observed irrespective of CYP2C19 loss-of-function polymorphisms. Our data suggests that adjusted-dose prasugrel and aspirin is a feasible treatment option in Japanese patients treated with EESs in elective PCI.

Topics: Aged; Aged, 80 and over; Aspirin; Coronary Artery Disease; Cytochrome P-450 CYP2C19; Drug-Eluting Stents; Everolimus; Female; Humans; Japan; Logistic Models; Male; Middle Aged; Multivariate Analysis; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Polymorphism, Genetic; Postoperative Complications; Prasugrel Hydrochloride; Prospective Studies; Thrombosis; Ticlopidine; Tomography, Optical Coherence

Dual antiplatelet therapy (DAPT) prevents thrombotic events after coronary stent implantation but may induce bleedings, specifically in elderly patients. However, a competitive risk analysis is lacking.. To assess the determinants of major bleeding and the balance between the competing risks of major bleeding and thrombotic events during prasugrel-based DAPT after stent implantation.. Overall, 2,291 patients randomized to drug-eluting or bare metal stents and treated with prasugrel 10mg/day for 1 year were followed over 2 years for major bleeding (BARC 3/5) and thrombotic events (cardiac death, myocardial infarction, definitive/probable stent thrombosis). Prasugrel dose was reduced to 5mg in patients >75 years and/or <60kg. Predictors of major bleeding and competing risks of major bleeding and thrombotic events were assessed.. Two-year rates of major bleeding and thrombotic events were 2.9% and 9.0%, respectively. The only independent predictor of major bleeding was age (hazard ratio per year increase 1.05 [1.02,1.07], p<0.001). The relationship between major bleeding and age was non-linear, with lowest hazard ratios at 57 years and an exponential increase only above 65 years. In contrast, the relationship between thrombotic events and age was linear and continuously increasing with older age. While the competing risk of thrombotic events was higher than that of major bleeding in younger patients, the two risks were similar in older patients. After discontinuation of prasugrel, bleeding events leveled off in all patients, while thrombotic events continued to increase.. In prasugrel-based DAPT, age is the strongest risk factor for major bleeding, increasing exponentially >65 years. In younger patients, thrombotic events represent a higher risk than bleeding, while thrombotic and bleeding risks were similar in older patients. Important clinical implications relate to prasugrel dose in the elderly, duration of DAPT and the competing risk balance necessitating individualized treatment decisions.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Aspirin; Drug Therapy, Combination; Drug-Eluting Stents; Female; Hemorrhage; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Proportional Hazards Models; Retrospective Studies; Risk Factors; Stents; Thrombosis

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

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

The POPular Risk Score was developed for the selective intensification of P2Y. In a single-center prospective cohort study, patients with a high risk score were treated with prasugrel and patients with a low risk score with clopidogrel. The risk score-guided cohort was compared with a historic cohort of clopidogrel-treated patients. The endpoint consisted of all-cause death, myocardial infarction, stroke, or stent thrombosis during 1 year of follow-up. TIMI major and minor bleeding events were also analyzed.. The guided cohort contained 1127 patients, 26.9% of whom were switched to prasugrel according to the POPular Risk Score. The historic cohort contained 893 patients. The incidence of the combined thrombotic endpoint was significantly lower in the guided cohort as compared with the historic cohort (8.4% versus 3.7%, p < 0.001). This strategy was safe with respect to bleeding (4.0% versus 1.3%, p < 0.001, for TIMI major or minor bleeding). Results were comparable after multivariate and propensity score matched and weighted analysis.. Selective intensification of P2Y

Topics: Aged; Clopidogrel; Cytochrome P-450 CYP2C19; Female; Genotype; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Function Tests; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Risk; Stroke; Thrombosis

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

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

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

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

The maintenance dose of adjusted prasugrel 2.5 mg/day seems to be one option in ACS patients at high bleeding risk.

Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Female; Hemorrhage; Hospitalization; Humans; Japan; Male; Middle Aged; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prognosis; Prospective Studies; Risk Factors; Stents; Thrombosis

Recent studies suggested protruding thrombus and atheroma after stent placement could be a substrate for subsequent adverse ischemic events. Although protruded atherothrombotic burden can be assessed as intra-stent tissue (IST) by optical coherence tomography (OCT), the effects of potent antiplatelet therapy on the acute phase resolution of IST in patients with acute coronary syndrome (ACS) was unknown.. Ninety-six consecutive ACS patients with multi-vessel disease were enrolled in this prospective registry. In combination with aspirin, either clopidogrel or prasugrel was selected according to the date of enrolment. OCT examination was done immediately after percutaneous coronary intervention (post-PCI) and 10 days after index PCI (follow-up acute phase) to calculate averaged IST score as semi-quantitative measures of IST. High residual platelet reactivity (HRPR) was defined as platelet reactivity units (PRU)≥240 by VerifyNow P2Y12 assay (Accumetrics Inc., San Diego, CA, USA).. Thirty two patients (38 stents) were enrolled in the prasugrel group and sixty four patients (72 stents) in the clopidogrel group. Averaged IST scores post-PCI were similar between the two groups (0.68±0.41 vs. 0.68±0.40, p=0.99), which decreased in all of the prasugrel group and in 87.5% of the clopidogrel group (p=0.02). Consequently, changes in averaged IST score (delta averaged IST score) were significantly greater in the prasugrel group compared to those in the clopidogrel group (-0.411±0.288 vs. -0.299±0.270, p=0.045). The frequency of HRPR was significantly lower in the prasugrel group (10.0% vs 32.4%, p=0.028).. Prasugrel plus aspirin achieved greater acute phase reduction of IST than clopidogrel plus aspirin, which might underlie the clinical benefit of potent antiplatelet therapy in ACS. (UMIN000018751).

Topics: Acute Coronary Syndrome; Aged; Aspirin; Blood Platelets; Clopidogrel; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Plaque, Atherosclerotic; Platelet Aggregation Inhibitors; Postoperative Complications; Prasugrel Hydrochloride; Prospective Studies; Registries; Stents; Thrombosis; Tomography, Optical Coherence; Treatment Outcome

It is known that physical exercise may increase platelet activity. However, the effect of exercise on platelet reactivity in patients on dual antiplatelet therapy has not been investigated yet. In our study, 21 patients with coronary artery disease on dual antiplatelet therapy and 10 controls were enrolled. We performed an exercise test using a cycle ergometer and determined the adenosine diphosphate-induced platelet reactivity before and immediately after exercise testing. Additionally, we analysed maximal exercise capacity and an electrocardiogram. Further, we assessed chromogranin A and P-selectin levels and platelet counts.

Topics: Adenosine Diphosphate; Aspirin; Chromogranin A; Clopidogrel; Coronary Artery Disease; Electrocardiography; Exercise; Exercise Tolerance; Humans; P-Selectin; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Count; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Stents; Thrombosis; Ticlopidine

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

Prasugrel has proved its superiority over clopidogrel for reducing ischemic events among patients with ST elevation myocardial infarction (STEMI) undergoing urgent percutaneous coronary intervention (PCI). Data on switching of antiplatelet therapy in acute coronary syndrome patients in clinical practice are very limited. Importantly, the safety of in-hospital switching from clopidogrel to prasugrel following thrombolysis has not been addressed.. We reviewed consecutive STEMI patients from February 2011 to April 2014 who were transferred to a tertiary center after receiving thrombolysis and a loading dose of clopidogrel in a non-PCI-capable center. If not contraindicated, these patients were reloaded and treated with prasugrel. A control group, three times larger, was selected from patients who underwent primary PCI and were initially treated with prasugrel. In-hospital outcomes were examined.. Cases (n=45, 13% female, mean age 56 years) and controls (n=135, 11% female, mean age 54 years) did not differ significantly with respect to MI location, left ventricular systolic function, and extent of coronary artery disease. Mean time from thrombolysis to prasugrel loading was 32±19 hours. No significant differences were found between cases and controls in TIMI major or minor bleeding (0% vs. 3%), overall mortality (0% vs. 1.5%), and hospitalization length (4.8 vs. 5.5 days).. In-hospital reloading and subsequent maintenance therapy with prasugrel in patients who received thrombolysis and a loading dose of clopidogrel appears to be as safe as in STEMI patients managed by primary PCI; however, larger studies are needed to verify these results.

Topics: Aged; Clopidogrel; Female; Hospitalization; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Prasugrel Hydrochloride; ST Elevation Myocardial Infarction; Tertiary Healthcare; Thrombosis; Ticlopidine

The efficacy of P2Y12 inhibition for the prevention of cardiovascular events in patients with peripheral arterial disease (PAD) has been established. However, the therapeutic effects on ischemic limb complications are less clear. Accordingly, we aimed to develop a novel murine model of thrombotic hindlimb ischemia to reflect that found in patients with PAD exhibiting ischemic limb symptoms. We further investigated the effects of P2Y12 deficiency and P2Y12 inhibition by prasugrel in this model.. Thrombus formation induced by application of ferric chloride to the femoral artery resulted in a significant reduction in blood flow in the injured limb. In gait analysis using the CatWalk system, moderate difficulties in grounding and weight bearing of the ischemic limb, including reduction of maximum contact area and stance phase duration and increasing in swing phase duration in the ischemic limb, were observed in this model. Blood flow reduction and gait abnormalities gradually recovered over 21 days to levels present before arterial injury. Compared to wild-type (WT) mice, significant increases in blood flow and improvement in gait were observed in P2Y12-deficient mice. In addition, daily oral administration of prasugrel (3 mg/kg per day) to WT mice resulted in significant inhibition of blood flow reduction and gait abnormalities to levels found in P2Y12 deficient mice.. Acute femoral artery thrombosis resulted in hindlimb ischemia and moderate gait abnormalities in mice. In addition, the present study suggests a possible role of P2Y12 in the complications with thrombotic limb ischemia.

Topics: Animals; Disease Models, Animal; Gait; Hindlimb; Ischemia; Mice; Mice, Inbred C57BL; Mice, Knockout; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Regional Blood Flow; Thrombosis

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

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

Antiplatelet switching in the management of acute coronary syndrome (ACS) seems to be safe, but prospective data are limited. This retrospective study assessed the safety and efficacy of in-hospital clopidogrel-to-prasugrel switching in patients with ACS. We analysed 525 consecutive patients with ACS admitted to our coronary care unit. We assessed the prevalence and the short-term outcomes of in-hospital clopidogrel-to-prasugrel switching. Bleeding and thrombotic events were assessed using propensity score matching analysis. A total of 468 patients received acetylsalicylic acid and a P2Y12 ADP receptor inhibitor. Medication switching occurred in 117 patients (25 %). Compared with the clopidogrel group, the switching group consisted preferentially of younger males with STEMI, exhibited fewer comorbidities, and had lower ischaemic risk. We found no differences between the switching group and the clopidogrel group in the bleeding rate [3.6 vs. 2.3 %, odds ratio (OR):1.59 95 % confidence interval (CI): 0.26-9.7, p NS], and in adverse cardiac or cerebrovascular events (MACCE) (5 vs. 8.4 %, OR: 0.57 95 % CI 0.16-2, p NS). In-hospital switching from clopidogrel to prasugrel in a selected high-risk ACS population resulted in a similar incidence of in-hospital haemorrhagic and thrombotic events. This strategy should be clarified in further randomised studies.

Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Aspirin; Clopidogrel; Drug Substitution; Female; Hemorrhage; Humans; Male; Middle Aged; Prasugrel Hydrochloride; Receptors, Purinergic P2Y12; Sex Factors; Thrombosis; Ticlopidine

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

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

Several clinical trials have demonstrated the benefits of thienopyridine monotherapy in ischaemic stroke patients. Non-human primate models of ischaemic stroke have been used for various antithrombotic agents; however, to the best of our knowledge, there is no data on the effects of P2Y12 antagonists in models, such as the thrombotic middle cerebral artery occlusion (MCAO) monkey model. Accordingly, it remains unclear what level of inhibition of platelet aggregation (IPA) is required for optimal treatment of ischaemic stroke. In the present study, we investigated the effects of prasugrel, a third-generation thienopyridine antiplatelet drug, on platelet aggregation, thrombus formation and cerebral infarct volume in a non-human primate model. Daily oral administration of prasugrel resulted in significant and stable platelet inhibitory effects on Day 3, with IPA values ranging from 31% to 36% at 0.3mg/kg/day and from 44% to 50% at 1mg/kg/day. These IPA levels encompassed values observed in clinical trials of clopidogrel, and were thus selected for further study. In the thrombotic MCAO model, prasugrel increased MCA patency in a dose-dependent manner and significantly reduced ischaemic infarct volume by approximately 70% at 0.3mg/kg/day and 90% at 1mg/kg/day without increasing haemorrhagic infarction. Prasugrel also significantly reduced neurological deficit scores by 60% at 0.3mg/kg/day and 80% at 1mg/kg/day. In conclusion, prasugrel treatment resulted in effective reduction of ischaemic infarction and an associated improvement in neurological function without increasing haemorrhagic infarction. These data suggest that prasugrel monotherapy would be effective for the prevention of thrombotic stroke.

Topics: Adenosine Diphosphate; Administration, Oral; Animals; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Haplorhini; Hemorrhage; Infarction, Middle Cerebral Artery; Macaca fascicularis; Male; Myocardial Ischemia; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Stroke; Thrombosis; Time Factors

The present study examined the effects of prasugrel in a mouse model of thrombosis-induced neointimal hyperplasia. Following carotid artery injury by application of ferric chloride solution, thrombus formation was assessed on Day 1 and neointimal thickening was assessed on Day 21. Single administrations of prasugrel at 0.3-3mg/kg (p.o.) resulted in a dose-related and sustained inhibition of ADP-induced platelet aggregation through 24h. Single and multiple (1 and 3 weeks) administration of prasugrel (3mg/kg loading and 1mg/kg/day maintenance doses) resulted in a marked inhibition of neointimal thickening in the injured artery. In the dose-response study, a single administration of prasugrel at 0.3-3mg/kg (p.o.) dose-relatedly inhibited thrombus formation and neointimal thickening on Days 1 and 21, respectively. The degree of neointimal hyperplasia in the injured artery correlated significantly with the thrombus indices, time to occlusion and patency rate. To explore possible mechanisms of inhibition of neointimal hyperplasia by prasugrel, mRNA expression levels of inflammatory and fibrosis markers were determined in injured arteries. Prasugrel treatment resulted in reduced MCP-1, ICAM-1 and TGF-β mRNA levels on Day 2 (24h after the injury) and Day 8 (1 week after the injury) in the target arteries. In conclusion, we found that a single oral loading dose of prasugrel markedly prevented neointimal hyperplasia by inhibiting platelet activation and thrombus formation and was associated with inhibition of the expression of inflammatory and fibrosis markers, including MCP-1, ICAM-1 and TGF-β, in the injured arteries.

Topics: Adenosine Diphosphate; Animals; Aorta; Arterial Occlusive Diseases; Arteries; Carotid Arteries; Chemokine CCL2; Chlorides; Ferric Compounds; Hyperplasia; Inflammation; Intercellular Adhesion Molecule-1; Mice; Mice, Inbred C57BL; Neointima; Platelet Aggregation; Prasugrel Hydrochloride; Pyridines; RNA, Messenger; Thrombosis; Time Factors; Transforming Growth Factor beta1

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

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

This study sought to evaluate the impact of treatment with prasugrel and high-dose clopidogrel on the basis of platelet function testing in patients with acute coronary syndrome (ACS) who are undergoing percutaneous coronary intervention (PCI).. The clinical impact of treatment with prasugrel in patients with ACS who have high platelet reactivity (HPR) is unknown.. Patients with ACS who were pre-treated with clopidogrel and undergoing successful PCI were enrolled in a single-center, prospective registry. Platelet function was measured 12 to 36 h after PCI with the Multiplate device (Roche Diagnostics GmbH, Mannheim, Germany). Patients with HPR (>46 U) were switched to prasugrel or treated with high-dose clopidogrel, and those without HPR continued treatment with 75 mg of clopidogrel.. A total of 741 consecutive patients were enrolled in the study between September 2011 and August 2012, and 219 of these patients (29.5%) had HPR. Although platelet reactivity decreased after treatment adjustments in those with HPR, prasugrel provided significantly more potent platelet inhibition compared with high-dose clopidogrel (p < 0.0001). Compared with patients without HPR, the risk of all-cause death, myocardial infarction, stent thrombosis, or stroke at 1 year was significantly higher in the high-dose clopidogrel group (hazard ratio [HR]: 2.27; 95% confidence interval [CI]: 1.45 to 3.55; p < 0.0001), and patients who were switched to prasugrel had similar outcomes (HR: 0.90; 95% CI: 0.44 to 1.81; p = 0.76). Bleeding Academic Research Consortium (BARC) type 3/5 bleeding was also more frequent in patients treated with high-dose clopidogrel (HR: 2.09; 95% CI: 1.05 to 4.17; p = 0.04) than in patients switched to prasugrel (HR: 0.45; 95% CI: 0.11 to 1.91; p = 0.28). In a multivariate model, HPR with high-dose clopidogrel, but not with prasugrel, was an independent predictor of the composite ischemic endpoint (HR: 1.90; 95% CI: 1.17 to 3.08; p = 0.01).. Switching patients with ACS who have HPR to treatment with prasugrel reduces thrombotic and bleeding events to a level similar to that of those without HPR; however, there is a higher risk of both thrombotic and bleeding complications with high-dose clopidogrel.

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Cause of Death; Clopidogrel; Combined Modality Therapy; Confidence Intervals; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Piperazines; Platelet Function Tests; Prasugrel Hydrochloride; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Purinergic P2Y Receptor Antagonists; Registries; Risk Assessment; Severity of Illness Index; Stents; Stroke; Survival Rate; Thiophenes; Thrombosis; Ticlopidine; Treatment Outcome

Stent thrombosis is a morbid complication after percutaneous coronary intervention. Dual antiplatelet therapy significantly reduces stent thrombosis risk and forms currently the basis in acute ST elevation myocardial infarction pharmacologic treatment. The introduction of clopidogrel has made a major advance in the acute coronary syndrome treatment. However, there is growing evidence about failure in antiplatelet response after clopidogrel, which may lead to subsequent risk of future thrombotic events. The antiplatelet inhibitory effect of clopidogrel varies widely among individuals. High on-treatment platelet reactivity has been repeatedly associated with a hazard for cardiovascular events, including stent thrombosis. Laboratory monitoring of antiplatelet therapy efficacy may help identify patients with insufficient antiplatelet response. Prasugrel therapy was repeatedly described as an effective method to overcome clopidogrel resistance. We report a case of diabetic patient in whom myocardial reinfarction due to stent thrombosis developed. Clopidogrel resistance was detected in this patient using light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation assessment. After prasugrel administration, no other ischemic event occurred, and patient was released to outpatient care in good general condition.

Topics: Aged, 80 and over; Aspirin; Clopidogrel; Coronary Angiography; Diabetes Mellitus, Type 2; Drug Resistance; Electrocardiography; Heparin; Humans; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Stents; Thiophenes; Thrombosis; Ticlopidine

Topics: Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Arteriovenous Malformations; Aspirin; Drug Therapy, Combination; Fatal Outcome; Gastrointestinal Hemorrhage; Humans; Intracranial Hemorrhages; Male; Middle Aged; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Stents; Thiophenes; Thrombosis; Warfarin

Although randomized clinical trials have compared clopidogrel with higher potency ADP receptor inhibitors (ADPris) among patients with myocardial infarction, little is known about the frequency and factors associated with switching between ADPris in clinical practice.. We studied 47 040 patients with myocardial infarction treated with percutaneous coronary intervention, who received either clopidogrel or prasugrel within 24 hours of admission at 361 US hospitals from July 2009 to June 2011 using the merged Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines and CathPCI Registry database. Hierarchical logistic regression modeling was used to determine factors independently associated with in-hospital ADPri switching. Among 40 531 patients treated initially in-hospital with clopidogrel, 2125 (5.2%) were discharged on prasugrel; this frequency steadily increased from 0% to 7% during the study period. Among 6509 patients treated initially in-hospital with prasugrel, 751 (11.5%) were discharged on clopidogrel. The frequency of this switch increased from 6% to 18% during the first 2 quarters of the study period and decreased to 9% by the end. Switching clopidogrel to prasugrel was associated with high-risk angiographic characteristics (thrombotic, long, and bifurcating lesions), reinfarction in-hospital, and private health insurance coverage. Older age, previous cerebrovascular event, in-hospital coronary artery bypass grafting, in-hospital bleeding, and warfarin use at discharge were associated with switching prasugrel to clopidogrel.. Clopidogrel and prasugrel are not uncommonly switched in-hospital in patients with myocardial infarction undergoing percutaneous coronary intervention. In contemporary US practice, in addition to risk for bleeding and recurrent ischemic events, medical drug coverage is a major determinant of ADPri selection.

Topics: Acute Disease; Age Factors; Aged; Clopidogrel; Drug Substitution; Female; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Piperazines; Postoperative Complications; Practice Guidelines as Topic; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Recurrence; Registries; Risk Factors; Thiophenes; Thrombosis; Ticlopidine; United States

In patients with acute myocardial infarction undergoing reperfusion therapy to restore blood flow through blocked arteries, simultaneous inhibition of platelet P2Y12 receptors with the current standard of care neither completely prevents recurrent thrombosis nor provides satisfactory protection against reperfusion injury. Additionally, these antiplatelet drugs increase the risk of bleeding. To devise a different strategy, we engineered and optimized the apyrase activity of human nucleoside triphosphate diphosphohydrolase-3 (CD39L3) to enhance scavenging of extracellular adenosine diphosphate, a predominant ligand of P2Y12 receptors. The resulting recombinant protein, APT102, exhibited greater than four times higher adenosine diphosphatase activity and a 50 times longer plasma half-life than did native apyrase. Treatment with APT102 before coronary fibrinolysis with intravenous recombinant human tissue-type plasminogen activator in conscious dogs completely prevented thrombotic reocclusion and significantly decreased infarction size by 81% without increasing bleeding time. In contrast, clopidogrel did not prevent coronary reocclusion and increased bleeding time. In a murine model of myocardial reperfusion injury caused by transient coronary artery occlusion, APT102 also decreased infarct size by 51%, whereas clopidogrel was not effective. These preclinical data suggest that APT102 should be tested for its ability to safely and effectively maximize the benefits of myocardial reperfusion therapy in patients with arterial thrombosis.

Topics: Adenosine Diphosphate; Animals; Apyrase; Clopidogrel; Coronary Circulation; Dogs; Fibrinolysis; Hemorrhage; Humans; Mice, Inbred C57BL; Myocardial Infarction; Myocardial Reperfusion Injury; Piperazines; Platelet Aggregation; Prasugrel Hydrochloride; Risk Factors; Thiophenes; Thrombosis; Ticlopidine; Time Factors; Tissue Plasminogen Activator; Treatment Outcome; Vascular Patency

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

Topics: Aspirin; Clopidogrel; Drug-Eluting Stents; Female; Humans; Male; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes; Thrombosis; Ticlopidine

In primary angioplasty, bivalirudin is superior to treatment with heparin plus glycoprotein inhibitors for reducing cardiovascular events, although bivalirudin increases the risk of stent thrombosis. Our hypothesis is that the use of prasugrel plus bivalirudin in primary angioplasty would reduce stent thrombosis and cardiovascular events.. Consecutive patients with acute ST-segment elevation myocardial infarction who were treated by primary angioplasty within 12 hours of the onset of symptoms received bivalirudin plus clopidogrel (Group A) or bivalirudin plus prasugrel (Group B). We compared the groups using propensity score matching. The combined end-point was cardiac death, thrombosis, acute myocardial infarction, and cerebrovascular accident at 30 days.. We assessed 168 patients. The approach was preferentially radial (95.7%). No differences in baseline characteristics were observed between Groups A (n = 70) and B (n = 70). The total mortality and rate of major bleeding complications at 30 days were 0% for both of the groups. The rate of acute and subacute thrombosis was 4.3% in Group A and 0% in Group B (P = 0.08). We observed an increased rate of events in Group A (5.7%) versus Group B (0%) (P = 0.042).. The administration of bivalirudin plus prasugrel in primary percutaneous coronary intervention reduces cardiovascular effects compared to bivalirudin plus clopidogrel without increasing major bleeding complications during the first 30 days following primary angioplasty performed with a preferentially radial approach.

Topics: Angioplasty; Antithrombins; Clopidogrel; Cohort Studies; Drug Combinations; Female; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Piperazines; Postoperative Complications; Prasugrel Hydrochloride; Recombinant Proteins; Retrospective Studies; Thiophenes; Thrombosis; Ticlopidine

Topics: Aryl Hydrocarbon Hydroxylases; Clopidogrel; Cytochrome P-450 CYP2C19; Drug Substitution; Heterozygote; Humans; Percutaneous Coronary Intervention; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes; Thrombosis; Ticlopidine

The CYP2C19 genotype is a predictor of adverse cardiovascular events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) treated with clopidogrel.. We aimed to evaluate the cost-effectiveness of a CYP2C19*2 genotype-guided strategy of antiplatelet therapy in ACS patients undergoing PCI, compared with two 'no testing' strategies (empiric clopidogrel or prasugrel).. We developed a Markov model to compare three strategies. The model captured adverse cardiovascular events and antiplatelet-related complications. Costs were expressed in 2010 US dollars and estimated using diagnosis-related group codes and Medicare reimbursement rates. The net wholesale price for prasugrel was estimated as $5.45 per day. A generic estimate for clopidogrel of $1.00 per day was used and genetic testing was assumed to cost $500.. Base case analyses demonstrated little difference between treatment strategies. The genetic testing-guided strategy yielded the most QALYs and was the least costly. Over 15 months, total costs were $18 lower with a gain of 0.004 QALY in the genotype-guided strategy compared with empiric clopidogrel, and $899 lower with a gain of 0.0005 QALY compared with empiric prasugrel. The strongest predictor of the preferred strategy was the relative risk of thrombotic events in carriers compared with wild-type individuals treated with clopidogrel. Above a 47% increased risk, a genotype-guided strategy was the dominant strategy. Above a clopidogrel cost of $3.96 per day, genetic testing was no longer dominant but remained cost-effective.. Among ACS patients undergoing PCI, a genotype-guided strategy yields similar outcomes to empiric approaches to treatment, but is marginally less costly and more effective.

Topics: Acute Coronary Syndrome; Aryl Hydrocarbon Hydroxylases; Cerebrovascular Disorders; Clopidogrel; Computer Simulation; Cost-Benefit Analysis; Cytochrome P-450 CYP2C19; Decision Support Techniques; Disease-Free Survival; Drug Costs; Gene Frequency; Genetic Predisposition to Disease; Genetic Testing; Health Care Costs; Hemorrhage; Humans; Insurance, Health, Reimbursement; Kaplan-Meier Estimate; Markov Chains; Medicare; Models, Economic; Myocardial Infarction; Percutaneous Coronary Intervention; Pharmacogenetics; Phenotype; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Predictive Value of Tests; Quality-Adjusted Life Years; Risk Assessment; Risk Factors; Thiophenes; Thrombosis; Ticlopidine; Time Factors; Treatment Outcome; United States

Prevention of intracranial stent thrombosis with dual-antiplatelet therapy is widely used in neuroendovascular procedures. However, the rising incidence of inadequate platelet inhibition with clopidogrel may increase complications following stent placement, especially with newer devices that possess a larger total metal surface area. While there are recent reports of prasugrel as an alternative to clopidogrel, there is no clinical evidence in neurointerventional patients regarding the use of a lower maintenance dose as an alternative strategy to gain adequate platelet inhibition while possibly reducing the risk of bleeding. We present 6-month efficacy and safety outcomes of two patients undergoing elective pipeline embolisation that were found to have inadequate platelet response to clopidogrel and subsequently transitioned to prasugrel 5 mg daily for the prevention of stent thrombosis.

Topics: Carotid Artery, Internal, Dissection; Cerebral Angiography; Clopidogrel; Embolization, Therapeutic; Female; Follow-Up Studies; Humans; Intracranial Aneurysm; Middle Aged; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Stents; Thiophenes; Thrombosis; Ticlopidine; Treatment Outcome

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

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

Romiplostim is a thrombopoietin receptor agonist that increases platelet counts and restores platelet function in patients with chronic immune thrombocytopenia (ITP). Increase in platelet count and platelet activation has been associated with increased thromboembolic risk. The present case report describes an interesting case of acute stent thrombosis in a patient with chronic immune thrombocytopenic purpura (ITP) being treated with romiplostim.

Topics: Acute Disease; Aspirin; Chest Pain; Clopidogrel; Eptifibatide; Female; Humans; Middle Aged; Peptides; Piperazines; Platelet Aggregation Inhibitors; Platelet Count; Prasugrel Hydrochloride; Purpura, Thrombocytopenic, Idiopathic; Receptors, Thrombopoietin; Risk Factors; Stents; Thiophenes; Thrombosis; Ticlopidine; Ultrasonography, Interventional

Primary percutaneous coronary intervention (PCI) encompassing stent implantation is a mainstay in the management of acute ST-elevation myocardial infarction (STEMI). Despite refinements in techniques and devices, peri- and post-procedural antithrombotic therapy remains pivotal to prevent early and late thrombotic events, without unduly increasing bleeding risk. Concomitant dual antiplatelet therapy with aspirin and clopidogrel has been considered until recently the standard of care in terms of oral antiplatelet agents. However, most recently a novel and more potent thienopyridine, prasugrel, has been tested in randomized trials including patients with STEMI, and subsequently approved for clinical practice in Europe and North America. Despite its potent antithrombotic effect, prasugrel also carries a statistically significant increase in the risk of bleeding, especially in the elderly, those with low body weight, and previous stroke or transient ischemic attack. Thus, the use of prasugrel, as well as that of clopidogrel or ticagrelor, should best be individualized to maximize clinical benefits and minimize hazards.

Topics: Angioplasty, Balloon, Coronary; Arrhythmias, Cardiac; Combined Modality Therapy; Evidence-Based Medicine; Hemorrhage; Humans; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Precision Medicine; Purinergic P2Y Receptor Antagonists; Stents; Thiophenes; Thrombosis

Oral prasugrel (Effient(®); Efient(®)) provides rapid, potent inhibition of platelet aggregation. It is indicated (in combination with aspirin) for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). In the pivotal clinical trial in this patient population, prasugrel-based therapy was associated with a significantly lower incidence of ischemic events than clopidogrel-based therapy. However, the efficacy of prasugrel was offset by a higher risk of bleeding than clopidogrel, with patients aged ≥75 years, those weighing <60 kg and those with a history of stroke or transient ischemic attack at the greatest risk. Prasugrel appears to have an overall favorable risk : benefit ratio in ACS patients undergoing PCI who do not have these three easily identifiable clinical characteristics. Limited pharmacoeconomic analyses suggest that prasugrel-based therapy is an economically attractive treatment strategy relative to clopidogrel-based therapy from a US healthcare payer perspective.

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Clinical Trials as Topic; Clopidogrel; Economics, Pharmaceutical; Hemorrhage; Humans; Piperazines; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Risk Factors; Thiophenes; Thrombosis; Ticlopidine; United States

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

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

The antithrombotic therapy in patients with atherosclerotic vascular disease is subject of several new therapeutic approaches. Simultaneous treatment with aspirin and a thienopyridin (clopidogrel) represents the standard of care for patients with acute coronary syndrome and following coronary stenting recommended by many guidelines. Without true evidence this drug combination is used for the prevention of arterial thrombosis in many other vascular interventions (e.g. carotid stenting, aortic stenting, peripherial arterial stents). The main problems of dual antiplatelet therapy with aspirin and clopidogrel are the slow onset of action and the high interindividual variation in the degree of platelet inhibition. The thienopyridin prasugrel is a more potent platelet inhibitor with a more rapid onset of action and smaller interindividual variations in platelet inhibition. The therapeutic superiority of prasugrel with respect to coronary events and stent thromboses was proven in patients with acute coronary syndrome undergoing coronary interventions. Specifically patients with Diabetes mellitus and patients with ST-elevation myocardial infarction seemed to benefit most due to the improved inhibition of platelet activity. A higher rate of bleeding complications was seen in those over the age of 75 years and a body weight below 60 kg for which a daily dose of 5mg/day was approved. Further clinical studies with prasugrel in patients with non-invasively treated acute coronary syndromes are ongoing.

Topics: Evidence-Based Medicine; Fibrinolytic Agents; Humans; Piperazines; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Thiophenes; Thrombosis; Treatment Outcome

This case report describes recurrent drug-eluting stent thrombosis with documented laboratory hyporesponsiveness to clopidogrel. The use of escalating doses of clopidogrel prevented subsequent episodes, but the patient developed gastrointestinal intolerance and diffuse cutaneous reaction, which resolved completely with prasugrel. Impressively, prasugrel 10 mg daily achieved an even lower vasodilator-stimulated phosphoprotein platelet reactivity index compared to clopidogrel 300 mg daily. Our case highlights the importance of alternative P2Y12 receptor antagonists for patients receiving drug-eluting stents.

Topics: Angioplasty, Balloon, Coronary; Clopidogrel; Drug-Eluting Stents; Humans; Male; Middle Aged; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes; Thrombosis; Ticlopidine; Treatment Failure

Antiplatelet therapy is important in the prevention of thrombosis, a significant cause of morbidity and mortality that is associated with acute coronary syndrome. Current evidence supports the general acceptance of aspirin and clopidogrel as the standard of care for the management of all patients experiencing an acute coronary syndrome with or without percutaneous coronary intervention. Thienopyridine antiplatelet agents such as clopidogrel, when used alone and in combination with aspirin, are effective in preventing myocardial infarction and death. Prasugrel, a potent antiplatelet agent that was recently approved by the Food and Drug Administration, may have some advantages over other antiplatelet agents, owing to its rapid onset of action, higher degree of platelet inhibition, and decreased interpatient variability in pharmacokinetics and pharmacodynamics as compared with clopidogrel. However, further studies are required to assess the potential for increased bleeding in high-risk patients.

Topics: Acute Coronary Syndrome; Administration, Oral; Hemorrhage; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Risk Factors; Thiophenes; Thrombosis; Treatment Outcome

We report a case with a hypersensitivity reaction to clopidogrel that resolved after clopidogrel discontinuation and recurred on rechallenge. The reaction included fever, tachycardia, rash and mild angioedema. As an alternative to clopidogrel, the more potent thienopyridine prasugrel was administered without any signs of an allergic reaction in the hours, days and weeks following administration.

Topics: Aged; Angioedema; Clopidogrel; Drug Hypersensitivity; Exanthema; Fever; Humans; Male; Piperazines; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Tachycardia; Thiophenes; Thrombosis; Ticlopidine

Topics: Angioplasty, Balloon, Coronary; Antineoplastic Agents; Clopidogrel; Docetaxel; Drug Resistance; Drug-Eluting Stents; Humans; Male; Middle Aged; Piperazines; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Taxoids; Thiophenes; Thrombosis; Ticlopidine

Topics: Aged; Angiography; Aspirin; Clopidogrel; Coronary Thrombosis; Drug Resistance; Electrocardiography; Female; Femoral Artery; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes; Thrombosis; Ticlopidine

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

This report describes a case of an acute anterior myocardial infarction secondary to subacute stent thrombosis of a drug-eluting stent within the proximal segment of the left anterior descending artery (LAD) 5 days after percutaneous transluminal coronary angioplasty and stenting (PCI). The patient was initially managed with conventional dual-antiplatelet therapy (aspirin and clopidogrel) and was subsequently found to have complete absence of adenosine diphosphate (ADP) receptor P2Y12 receptor inhibition. Following additional PCI of the LAD and substitution of clopidogrel for the thienopyridine prasugrel, therapeutic platelet inhibition was achieved without recurrence of stent thrombosis.

Topics: Angioplasty, Balloon, Coronary; Anterior Wall Myocardial Infarction; Clopidogrel; Contraindications; Coronary Artery Disease; Drug Resistance; Drug-Eluting Stents; Humans; Male; Middle Aged; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Receptors, Purinergic P2Y12; Thiophenes; Thrombosis; Ticlopidine; Treatment Failure; Treatment Outcome

To report a case of successful use of prasugrel following percutaneous coronary intervention with placement of a bare metal stent in a patient with a documented hypersensitivity reaction to clopidogrel.. A 61-year-old male with a history of coronary artery disease with coronary stent placement presented with ST-elevation myocardial infarction. The patient had developed Stephens-Johnson syndrome 6 years earlier following clopidogrel administration, characterized by erythematous plaques and subsequent desquamation of the hands and feet; clopidogrel was discontinued and he was subsequently treated with ticlopidine in addition to aspirin. The third-generation thienopyridine prasugrel was initiated as a therapeutic alternative to clopidogrel after placement of a bare metal stent; a 60-mg dose was administered after extubation, followed by 10 mg/day. No signs of allergic reaction were observed in the days, weeks, and months following administration.. Thienopyridines, specifically clopidogrel, are the standard of care for prevention of coronary stent thrombosis; however, there are few data available on cross-hypersensitivity between these agents. One study demonstrated that 27% of patients who developed an allergic or hematologic reaction to clopidogrel developed a similar reaction to ticlopidine. Other therapeutic options for patients with clopidogrel hypersensitivity who are undergoing a percutaneous coronary intervention with stent placement include clopidogrel desensitization, warfarin plus aspirin, cilostazol, ticagrelor, and ticlopidine. However, these options are limited by efficacy and/or toxicity. With its approval in 2009, prasugrel has become a potential treatment option.. Prasugrel may be considered a therapeutic alternative in some patients allergic or intolerant to clopidogrel, but additional data are warranted to make a strong conclusion.

Topics: Angioplasty, Balloon, Coronary; Clopidogrel; Drug Hypersensitivity; Humans; Male; Middle Aged; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Stents; Thiophenes; Thrombosis; Ticlopidine; Treatment Outcome

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Cohort Studies; Drug Therapy, Combination; Female; Hemorrhage; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Piperazines; Prasugrel Hydrochloride; Recombinant Proteins; Stents; Thiophenes; Thrombosis; Time Factors

Dual antiplatelet therapy (DAT) has become standard care for patients undergoing percutaneous coronary intervention (PCI). Following balloon injury and stent placement, the intima at the site is distressed, resulting in the activation of coagulation cascade and platelets. In the case of bare metal stents (BMS), it takes six to eight weeks for the stent surface to be covered with neointima. However, in the case of a drug-eluting stent (DES), the process of healing is delayed and neointima may not form for months or even years. To prevent the formation of platelet thrombi, dual antiplatelet therapy is given as a combination of aspirin and clopidogrel for three months in a case of BMS and for a minimum of one year in a case of DES. A prolonged duration of therapy is often required for a subset of patients who are highly prone to thrombus formation. During most non-cardiac surgeries, dual antiplatelet therapy should be continued if bleeding can be directly controlled and excessive bleeding will have no adverse effect on the outcome of surgery. Prasugrel, another thienopyridine, is more potent and faster acting than clopidogrel, and is therefore of great value in cases of acute coronary syndrome during PCI, particularly in diabetics. Triple drug therapy, by adding cilastozol, is reserved for some selected thrombotic lesions. Ticagrelor and cangrelor are two new antiplatelet agents undergoing various clinical trials. (Cardiol J 2011; 18, 6: 712-717).

Topics: Angioplasty, Balloon, Coronary; Aspirin; Cilostazol; Clopidogrel; Coronary Restenosis; Drug Resistance; Drug Therapy, Combination; Drug-Eluting Stents; Hemorrhage; Humans; Metals; Patient Selection; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prosthesis Design; Risk Assessment; Risk Factors; Stents; Tetrazoles; Thiophenes; Thrombosis; Ticlopidine; Treatment Outcome

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

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Clopidogrel; Drug-Eluting Stents; Hemorrhage; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Stroke; Thiophenes; Thrombosis; Ticlopidine; Treatment Outcome

Topics: Acute Coronary Syndrome; Drug Interactions; Humans; Piperazines; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Thiophenes; Thrombosis

The new P2Y(12) antagonist prasugrel produces greater inhibition of ADP-induced platelet aggregation (IPA) and reduction of thrombotic events in patients versus approved doses of clopidogrel, but increases major bleeding. We examined whether IPA level or P2Y(12) receptor occupancy (RO) could be optimized to better balance the efficacy and bleeding effects of these thienopyridines and reduce the response variability in rabbits. Rabbits were given three daily oral doses of clopidogrel (0.3-30 mg/kg/d), prasugrel (0.03-10 mg/kg/d) or vehicle (n = 6-40/group). Electrically-induced carotid artery thrombosis (AT, % thrombus weight reduction), cuticle bleeding time (BT, fold-increase over control), IPA to 20 microM ADP (% inhibition of peak light transmission) and RO (% inhibition of [(33)P]-2MeS-ADP binding to P2Y(1)-blocked platelets) were determined 2-3 hours after the last dose. ED(50) (doses for half-maximal effect, mg/kg/d) of AT, BT, IPA and RO were 1.6, 6.7, 1.9 and 1.4 for clopidogrel vs. 1.2, 1.9, 0.5 and 0.2 for prasugrel. IPA of 30-40% for both compounds produced the optimal balances of efficacy (AT: 50-60%) and BT of about 2-fold with significant RO of 70-80%. IPA of 50-60% achieved higher efficacy (AT: 60-80%), but with increased BT of five- to six-fold and >90% RO. Box-plot suggests no significant difference in the IPA and RO response variability between both compounds. Clopidogrel was 1.3-7 times less potent than prasugrel in rabbits, depending upon which biomarker was studied. The ratio of efficacy: bleeding was most favorable at a moderate IPA of 30% to 40%. Both compounds had similar IPA and RO response variability.

Topics: Adenosine Diphosphate; Administration, Oral; Animals; Binding, Competitive; Bleeding Time; Clopidogrel; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrinolytic Agents; Hemorrhage; Hemostasis; Male; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Rabbits; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Thionucleotides; Thiophenes; Thrombosis; Ticlopidine

Topics: Blood Platelets; Colorectal Neoplasms; Fibrinolysis; Humans; Incidence; Piperazines; Platelet Aggregation; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Risk Factors; Thiophenes; Thrombosis; United States

Topics: Clopidogrel; Commerce; Drug Costs; Humans; Insurance, Pharmaceutical Services; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes; Thrombosis; Ticlopidine

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

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

Topics: Aspirin; Dose-Response Relationship, Drug; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Randomized Controlled Trials as Topic; Stents; Thiophenes; Thrombosis

Antiplatelet and antithrombotic activity of multiple oral dosing of prasugrel were evaluated in several animal species. Prasugrel's active metabolite concentration-relatedly inhibited in vitro ADP-induced aggregation of rat, rabbit, dog, monkey and human platelets. Oral administration of prasugrel to dogs (0.03-0.3 mg/kg/day) and monkeys (0.1 and 0.3 mg/kg/day) once a day for 14 days resulted in potent, dose-related and cumulative inhibition of ADP-induced platelet aggregation. The inhibitory effects reached a plateau on days 3 to 5 and thereafter were maintained during dosing. Inhibition decreased gradually after cessation of dosing with near full recovery by 7 days after last dose. Antiplatelet and antithrombotic activity of prasugrel and clopidogrel were further examined in rats. Multiple oral dosing of prasugrel (0.3-3 mg/kg/day) to rats resulted in more potent inhibition of platelet aggregation compared to clopidogrel (3-30 mg/kg/day) and ticlopidine (30-300 mg/kg/day). Separate experiments confirmed that platelet inhibition was associated with inhibition of [(3)H]-2-methylthio-ADP binding to rat platelets. In a rat model of electrically-induced arterial thrombosis, prasugrel (0.1-1 mg/kg/day, p.o.) significantly prolonged the time to arterial occlusion and increased the duration of arterial patency. The inhibition of platelet aggregation of prasugrel was about 10 and 300 times more potent than clopidogrel and ticlopidine, respectively. Overall these results show that in several species multiple oral administration of prasugrel results in more potent inhibition of platelet aggregation and thrombus formation than clopidogrel and ticlopidine, and that these effects are mediated by inhibition of platelet ADP receptors.

Topics: Administration, Oral; Adult; Animals; Clopidogrel; Dogs; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; In Vitro Techniques; Macaca fascicularis; Male; Middle Aged; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Rabbits; Rats; Rats, Sprague-Dawley; Species Specificity; Thiophenes; Thrombosis; Ticlopidine

Topics: Acute Coronary Syndrome; Clopidogrel; Coronary Disease; Forecasting; Hemorrhage; Humans; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Stroke; Thiophenes; Thrombolytic Therapy; Thrombosis; Ticlopidine

The novel thienopyridine prodrug prasugrel, a platelet P2Y(12) ADP receptor antagonist, requires in vivo metabolism for activity. Although pharmacological data have been collected on the effects of prasugrel on platelet aggregation, there are few data on the direct effects of the prasugrel's active metabolite, R-138727, on other aspects of platelet function. Here we examined the effects of R-138727 on thrombo-inflammatory markers of platelet activation, and the possible modulatory effects of other blood cells, calcium, and aspirin. Blood (PPACK or citrate anticoagulated) from healthy donors pre- and post-aspirin was incubated with R-138727 and the response to ADP assessed in whole blood or platelet-rich plasma (PRP) by aggregometry and flow cytometric analysis of leukocyte-platelet aggregates, platelet surface P-selectin, and GPIIb-IIIa activation. Low-micromolar concentrations of R-138727 resulted in a rapid and consistent inhibition of these ADP-stimulated thrombo-inflammatory markers. These rapid kinetics required physiological calcium levels, but were largely unaffected by aspirin. Lower IC(50) values in whole blood relative to PRP suggested that other blood cells affect ADP-induced platelet activation and hence the net inhibition by R-138727. R-138727 did not inhibit P2Y(12)-mediated ADP-induced shape change, even at concentrations that completely inhibited platelet aggregation, confirming the specificity of R-138727 for P2Y(12). In conclusion, R-138727, the active metabolite of prasugrel, results in rapid, potent, consistent, and selective inhibition of P2Y(12)-mediated up-regulation of thrombo-inflammatory markers of platelet activation. This inhibition is enhanced in the presence other blood cells and calcium, but not aspirin.

Topics: Adenosine Diphosphate; Adult; Aspirin; Biomarkers; Blood Cells; Calcium; Cells, Cultured; Female; Humans; Inflammation; Kinetics; Male; Middle Aged; Piperazines; Platelet Activation; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Thiophenes; Thrombosis; Up-Regulation

1. CS-747 is a novel antiplatelet agent that generates an active metabolite, R-99224, in vivo. CS-747 itself was totally inactive in vitro. This study examined in vivo pharmacological profiles of CS-747 after single oral administration to rats. 2. Orally administered CS-747 (0.3 - 10 mg kg(-1)) partially but significantly decreased [(3)H]-2-methylthio-ADP binding to rat platelets. CS-747 (3 mg kg(-1), p.o.) treatment neutralized ADP-induced decreases of cyclic AMP concentrations induced by prostaglandin E(1), suggesting that metabolites of CS-747 interfere with G(i)-linked P2T receptor. 3. CS-747 (0.3 and 3 mg kg(-1), p.o.) markedly inhibited ex vivo washed platelet aggregation in response to ADP but not to thrombin. CS-747 also exhibited a marked inhibition of ADP-induced ex vivo platelet aggregation in PRP with a rapid onset (<0.5 h) and long duration (>3 days) of action (ED(50) at 4 h=1.2 mg kg(-1)). 4. R-99224 (IC(50)=45 microM) inhibited in vitro PRP aggregation in a concentration-related manner. 5. CS-747 prevented thrombus formation in a dose-related manner with an ED(50) value of 0.68 mg kg(-1). CS-747 was more potent than clopidogrel (6.2 mg kg(-1)) and ticlopidine (>300 mg kg(-1)). 6. CS-747, clopidogrel, and ticlopidine prolonged the bleeding time. The order of potency of these agents in this activity was the same as that in antiaggregatory and antithrombotic activities. 7. These findings indicate that CS-747 is an orally active and a potent antiplatelet and antithrombotic agent with a rapid onset and long duration of action, and warrants clinical evaluations of the agent.

Topics: Adenosine Diphosphate; Administration, Oral; Animals; Arteriovenous Shunt, Surgical; Binding, Competitive; Bleeding Time; Blood Platelets; Clopidogrel; Collagen; Cyclic AMP; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrinolytic Agents; Male; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2; Thionucleotides; Thiophenes; Thrombin; Thrombosis; Ticlopidine; Time Factors; Tritium