prasugrel-hydrochloride and Coronary-Disease

The duration and combination of dual antiplatelet therapy after coronary stent implantation, consisting of aspirin and a P2Y12 inhibitor, is among the most intensely investigated therapeutic strategies in cardiovascular medicine. While initial studies have mainly focused on the efficacy and safety of individual antithrombotic agents, the increased need for a personalized, risk-based approach to define the optimal duration of antithrombotic treatment according to the estimated ischemic and bleeding risk was then recognized. Recent recommendations for the optimal duration of antithrombotic combination therapies following coronary stent implantation in various clinical scenarios have substantially changed. The aim of the present article is to discuss the recent evidence from randomized clinical trials and observational studies with respect to antithrombotic treatment regimens in patients undergoing coronary artery stenting for stable coronary artery disease (CAD) or an acute coronary syndrome (ACS). We will focus on optimal treatment duration and a personalized approach based on ischemic and bleeding risk assessment.

Topics: Acute Coronary Syndrome; Aspirin; Clopidogrel; Coronary Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hemorrhage; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Risk Factors; Stents; Ticagrelor

Whether ticagrelor is superior to prasugrel in inhibiting platelet reactivity (PR) has remained unclear, possibly because different test methods have been used to determine this. Therefore, using a different test method, we performed a meta-analysis comparing the effects of ticagrelor and prasugrel on PR.. PubMed, Embase, Web of Science, and Google Scholar were searched - without language restrictions (last updated on 26 February 2017) - for randomized trials comparing the effects of prasugrel with those of ticagrelor in patients with coronary artery disease. Selected studies were chosen for pooled analysis according to the inclusion and exclusion criteria. Data are presented as mean difference (MD) and 95% confidence interval. For the loading dose, using the VerifyNow-P2Y12 (VN) test, the PR was similar for both the prasugrel and ticagrelor groups [MD=10.80 (-9.81-31.40), P=0.30]. Using the vasodilatorstimulated phosphoprotein test, the PR was also similar for both the ticagrelor and prasugrel groups [MD=-2.87 (-6.35-0.60), P=0.10]. For the maintenance dose, using the VN test, the PR was lower in the ticagrelor group than in the prasugrel group [MD=-43.37 (-60.53 to -26.21), P<0.01]. Finally, using the vasodilator-stimulated phosphoprotein test, the PR was lower in the ticagrelor group than in the prasugrel group [MD=-9.23 (-15.82 to -2.64), P<0.01].. There was no difference between ticagrelor and prasugrel in terms of PR under the loading dose, but ticagrelor had a lower degree of PR under the maintenance dose. The results were not affected by the different PR test methods.

Topics: Adenosine; Adult; Aged; Blood Platelets; Cell Adhesion Molecules; Chi-Square Distribution; Coronary Disease; Female; Humans; Male; Microfilament Proteins; Middle Aged; Odds Ratio; Percutaneous Coronary Intervention; Phosphoproteins; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Risk Factors; Ticagrelor; Treatment Outcome

Topics: Absorbable Implants; Acute Coronary Syndrome; Adenosine; Aftercare; Aged, 80 and over; Cardiac Imaging Techniques; Coronary Angiography; Coronary Artery Bypass; Coronary Disease; Diabetic Angiopathies; Drug Therapy, Combination; Fibrinolytic Agents; Fractional Flow Reserve, Myocardial; Graft Occlusion, Vascular; Humans; Out-of-Hospital Cardiac Arrest; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Prasugrel Hydrochloride; Prosthesis Design; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; ST Elevation Myocardial Infarction; Stents; Thrombectomy; Ticagrelor; Time-to-Treatment; Tissue Scaffolds

Topics: Acute Coronary Syndrome; Adenosine; Angioplasty, Balloon, Coronary; Aspirin; Clopidogrel; Coronary Disease; Drug Therapy, Combination; Early Medical Intervention; General Practice; Guideline Adherence; Humans; Male; Middle Aged; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Secondary Prevention; Stents; Thiophenes; Ticagrelor; Ticlopidine

The most common risks related to platelet inhibitor therapy are bleeding, drug-drug interactions and therapeutic failure. The new substances prasugrel and ticagrelor are more potent platelet inhibitiors than clopidogrel. This reduces the incidence of ischemic events, but also potentially increases the bleeding risk. Clopidogrel therapy has up to 20% non-response rates, which can partially be explained by genetic polymorphisms and drug-drug interactions. Currently no evidence exists that ticagrelor or prasugrel efficacy is affected by genetic polymorphisms. The therapy in patients at risk still has to be carefully adapted to minimize adverse events. Patients older than 75 years and/or weighing less than 60 kg should receive a reduced dose of prasugrel. The combination of ticagrelor with strong cytochrome-P450-3A4 inhibitors is contraindicated.. Blutungsereignisse, Arzneimittelwechselwirkungen und Therapieversagen sind relevante Risiken einer Therapie mit Plättchenaggregationshemmern. Die neuen Substanzen Prasugrel und Ticagrelor sind stärker wirksam als Clopidogrel und senken ischämische Ereignisse bei Patienten mit akutem Koronarsyndrom effizienter. Sie erhöhen allerdings potenziell auch die Blutungsraten. Eine Therapie mit Clopidogrel birgt das Risiko einer Therapieresistenz bei bis zu 20% der Patienten, die u. a. auf genetischen Polymorphismen und Arzneimittelinteraktionen beruht. Für Prasugrel und Ticagrelor bestehen keine Hinweise, dass genetische Polymorphismen die Wirksamkeit beeinflussen. In Risikosituationen muss die Therapie jedoch sorgfältig angepasst werden, um unerwünschte Wirkungen zu minimieren: So wird bei Patienten >75 Jahre und/oder einem Körpergewicht <60 kg aufgrund des erhöhten Blutungsrisikos eine Prasugrel-Dosisreduktion empfohlen. Ticagrelor ist in Kombination mit starken Cytochrom-P450–3A4-Hemmern kontraindiziert.. Les événements hémorragiques, les interactions médicamenteuses et l'échec de thérapie constituent les risques majeurs des traitements à base d'antiagrégants plaquettaires. Les substances nouvelles, prasugrel et ticagrelor, présentent un effet anitagrégant plus important et diminuent les épisodes ischémiques d'une manière plus efficacement que le clopidogrel. Cependent la possibilité existe d'une augmentation d'épisodes de saignement. Le risque de résistance à la thérapie atteint jusqu'à 20% pour les patients traités à base de clopidogrel, entre autre en raison de polymorphismes génétiques. Il n'existe pas d'evidence pour un mécanisme pareil pour le prasugrel et le ticagrelor. Dans certaines situations de risque par contre, une adaption du dosage est conseillée pour minimiser les effets secondaires négatifs: Chez les patients de plus de 75 ans, et/ou d'un poids corporel de moins de 60 kg, une réduction du dosage de prasugrel est conseillée en raison d'un risque élevé d'hémorragie. Il est contrindiqué d'utiliser ticagrelor en combinaison avec des inhibiteurs puissants du cytochrome-P450–3A4.

Topics: Adenosine; Angioplasty, Balloon, Coronary; Aspirin; Clopidogrel; Coronary Disease; Drug Interactions; Drug Resistance; Drug Therapy, Combination; Hemorrhage; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Randomized Controlled Trials as Topic; Risk Factors; Stents; Thiophenes; Ticagrelor; Ticlopidine

A number of randomized double-blind studies have been conducted for comparative assessment of the pharmacodynamic properties of high loading and maintenance doses of clopidogrel (600-900 mg loading dose and 150 mg maintenance dose) and standard dose of prasugrel (60 mg loading dose and 10 mg maintenance dose) in patients with coronary heart disease, including those with acute coronary syndrome. This review briefly discusses the trials ACAPULCO and PRINCIPLE-TIMI 44. Compared with high dose clopidogrel, prasugrel inhibited P2Y12-mediated platelet aggregation faster and to a greater extent. A difference between effects of clopidogrel and prasugrel emerged as soon as at 30 minutes after the loading dose. Antiplatelet effects of prasugrel were greater than those of clopidogrel both during first 2-4 hours after administration of loading dose, and during maintenance dosing. This may have important clinical implications.

Topics: Clopidogrel; Coronary Disease; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Thiophenes; Ticlopidine; Time Factors; Treatment Outcome

Patients commonly undergo noncardiac surgical procedures after implantation of a coronary stent. In the case where surgery cannot be deferred until completing the minimum duration of dual antiplatelet therapy, the Brigham and Women's Hospital Cardiac Catheterization Laboratory recommends using a glycoprotein IIb/IIIa bridging protocol to minimize the risk of perioperative ischemic events. We discuss our algorithm for managing antiplatelet agents, including the newer agents, prasugrel and ticagrelor, in patients undergoing noncardiac surgery after coronary stenting and present our glycoprotein IIb/IIIa bridging strategy along with a review of the relevant pharmacodynamic and clinical evidence.

Topics: Adenosine; Administration, Oral; Algorithms; Coronary Disease; Elective Surgical Procedures; Humans; Piperazines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Practice Guidelines as Topic; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Risk Assessment; Risk Factors; Stents; Thiophenes; Ticagrelor

In the European Union Ticagrelor has recently been approved, as another P2Y12-receptor antagonist in addition to clopidogrel and prasugrel, in [corrected] the drug treatment after coronary intervention. [corrected] Dual antithrombotic treatment must be given for 4 weeks after elective implantation [corrected] of bare-metal stents, or for at least 6 months [corrected] with acetylsalicylic acid (ASA) plus clopidogrel after implantation of a drug-eluding stent. After an acute coronary syndrome ASA and clopidogrel (or prasugrel or ticagrelor) must be given for 12 months. In patients requiring urgent oral anticoagulation essential triple-drug treatment should be given over as short a [corrected] space of time if possible. [corrected] Prasugrel and ticagrelor may, to protect against gastroduodenal bleeding, be given without restriction together with a proton-pump inhibitor. Preoperative coagulation management is essential for patients who have been on dual platelet-aggregation inhibitors, but premature withdrawal of this medication should be avoided.

Topics: Adenosine; Aftercare; Angioplasty, Balloon, Coronary; Anticoagulants; Aspirin; Clopidogrel; Coronary Disease; Drug Administration Schedule; Drug Approval; Drug Therapy, Combination; Drug-Eluting Stents; Gastrointestinal Hemorrhage; Humans; Myocardial Revascularization; Piperazines; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Prasugrel Hydrochloride; Proton Pump Inhibitors; Stents; Thiophenes; Ticagrelor; Ticlopidine

Topics: Adenosine; Angioplasty, Balloon, Coronary; Clinical Trials as Topic; Clopidogrel; Coronary Angiography; Coronary Disease; Coronary Occlusion; Coronary Restenosis; Drug-Eluting Stents; Foramen Ovale, Patent; Hospital Mortality; Humans; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Radiology, Interventional; Thiophenes; Thrombolytic Therapy; Ticagrelor; Ticlopidine; Treatment Outcome

Prasugrel (CS-747; LY-640315) is a novel, third-generation oral thienopyridine that is a specific, irreversible antagonist of the platelet adenosine 5'-diphosphate P2Y(12) receptor. Laboratory results with prasugrel support more potent antiplatelet effects, a lower incidence of interpatient variability in antiplatelet response, and a reduced time to onset of antiplatelet activity compared with clopidogrel. Phase II results indicate that prasugrel produces a greater antiplatelet effect than clopidogrel administered even at doses higher than the currently approved 300-mg loading dose and 75-mg/d maintenance dose. Recent phase III data show that prasugrel is superior to clopidogrel in preventing ischemic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention, although this was associated with a greater risk of bleeding.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Aspirin; Clinical Trials as Topic; Coronary Disease; Drug Therapy, Combination; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Thiophenes

Platelets possess three P2 receptors for adenine nucleotides: P2Y1 and P2Y12, which interact with ADP, and P2X1, which interacts with ATP. The interaction of adenine nucleotides with their platelet receptors plays an important role in thrombogenesis. The thienopyridine ticlopidine, an antagonist of the platelet P2Y12 ADP receptor, reduces the incidence of vascular events in patients at risk, but it also has some important drawbacks: a relatively high incidence of toxic effects; delayed onset of action; high inter-individual variability in response. Another thienopyridine, clopidogrel, has superseded ticlopidine, because it is an efficacious antithrombotic drug and is less toxic than ticlopidine. However, the high inter-patient variability in response still remains an important issue. These drawbacks justify the continuing search for agents that can further improve the clinical outcome of patients with atherosclerosis through greater efficacy and/or safety. A new thienopyridyl compound prasugrel, which is characterized by higher potency and faster onset of action compared with clopidogrel, is currently under clinical evaluation. Two direct and reversible P2Y12 antagonists, cangrelor and AZD6140, have very rapid onset and reversal of platelet inhibition, which make them attractive alternatives to thienopyridines, especially when rapid inhibition of platelet aggregation or its quick reversal are required. Along with new P2Y12 antagonists, inhibitors of the other platelet receptor for ADP, P2Y1, and of the receptor for ATP, P2X1, are under development and may prove to be effective antithrombotic agents.

Topics: Adenosine; Adenosine Monophosphate; Angina, Unstable; Animals; Blood Platelets; Clopidogrel; Coronary Disease; Coronary Thrombosis; Drug Interactions; Fibrinolytic Agents; Humans; Myocardial Infarction; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Randomized Controlled Trials as Topic; Receptors, Purinergic P2; Receptors, Purinergic P2X; Syndrome; Thiophenes; Ticagrelor; Ticlopidine

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

Clinical trials have demonstrated the superior clinical efficacy of dual antiplatelet therapy with a thienopyridine (a P2Y(12) receptor blocker) and aspirin (COX-1 inhibitor) in patients undergoing stenting as well as patients with acute coronary syndromes. However, clopidogrel treatment is associated with a wide response variability and non-responsiveness in selected patients. The latter phenomenon is linked to the occurrence of recurrent ischaemic events including stent thrombosis in the recent studies. Prasugrel is a new thienopyridine derivative that produces more potent platelet inhibition and a rapid onset of action that is associated with irreversible P2Y(12) receptor blockade. The latter properties of prasugrel may provide a superior alternative to clopidogrel, with less response variability and a decreased prevalence of non-responsiveness.

Topics: Adenosine Diphosphate; Animals; Aspirin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase III as Topic; Clopidogrel; Collagen; Coronary Disease; Drug Evaluation, Preclinical; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Drugs, Investigational; Humans; Piperazines; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prodrugs; Purinergic P2 Receptor Antagonists; Pyridines; Rats; Receptors, Purinergic P2Y12; Thiophenes; Ticlopidine

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

This randomized trial tested whether early loading with prasugrel can provide sufficient platelet inhibition even when given at the start of a 2-h infusion of cangrelor.. Effective platelet inhibition with intravenous cangrelor reduces the risk of ischemic complications during percutaneous coronary intervention (PCI). Transitioning to oral therapy with clopidogrel or prasugrel is only recommended after discontinuation of cangrelor due to drug interactions. Given the long half-life of prasugrel, this drug could achieve effective platelet inhibition even when given early under cangrelor and thereby prevent a transient gap in platelet inhibition.. This trial randomized 110 P2Y. The 3 groups were well balanced with respect to clinical parameters. One hour following discontinuation of cangrelor, the primary endpoint was seen in 65.0% of patients on clopidogrel versus 95.6% with ticagrelor and 93.3% with prasugrel (p for superiority of prasugrel vs. clopidogrel = 0.003; p of prasugrel vs. ticagrelor = 0.65). The 30-day incidence of ischemic and bleeding events was similar in all groups.. Prasugrel 60 mg given at the start of a 2-h infusion of cangrelor can provide a sufficient platelet inhibition post-cangrelor. This approach prevents the transient gap in platelet inhibition seen with oral loading after discontinuation of cangrelor. (Impact of Extent of Clopidogrel-Induced Platelet Inhibition during Elective Stent Implantation on Clinical Event Rate - Advanced Loading Strategies [ExcelsiorLOAD2]; DRKS00009739).

Topics: Adenosine; Adenosine Monophosphate; Administration, Oral; Aged; Blood Platelets; Clopidogrel; Coronary Disease; Drug Substitution; Female; Germany; Humans; Infusions, Intravenous; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Prospective Studies; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Stents; Ticagrelor; Ticlopidine; Time Factors; Treatment Outcome

We determined if high on-treatment platelet reactivity (HTPR) can be overcome on the day of percutaneous coronary intervention (PCI) in patients with or without previous maintenance thienopyridine therapy. Patients with HTPR, as defined as P2Y12 reaction units (PRU) >230, were switched to an alternate thienopyridine. Patients with HTPR undergoing PCI are at increased risk for ischemic complications. A total of 429 patients undergoing PCI with drug-eluting stents were enrolled. Patients on maintenance thienopyridine (n = 249) with PRU >230 were loaded with the alternative thienopyridine. Patients who were thienopyridine naïve (n = 180) were randomized to clopidogrel 600 (n = 90) or prasugrel 60 mg (n = 90). Patients with HTPR were loaded with the alternative agent. Patients on maintenance clopidogrel (n = 192) had a higher prevalence of HTPR compared with prasugrel (n = 57; 51% vs 4%, p <0.001). Patients on maintenance clopidogrel with HTPR (n = 98) who were loaded with prasugrel achieved PRU ≤230 in 97%. Thienopyridine-naïve patients loaded with clopidogrel had a higher prevalence of HTPR compared with prasugrel (37% vs 3%, p <0.001). Clopidogrel-loaded patients with HTPR (n = 33) who were reloaded with prasugrel achieved PRU ≤230 in 94%. All 3 prasugrel-loaded patients with HTPR treated with clopidogrel achieved PRU ≤230. Two patients experienced 30-day major adverse clinical events. One patient experienced Thrombolysis In Myocardial Infarction major bleeding. In conclusion, HTPR can be overcome in patients with and without previous maintenance thienopyridine therapy by identifying patients with HTPR and switching to an alternate thienopyridine.

Topics: Clopidogrel; Coronary Disease; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Pyridines; Risk Factors; Ticlopidine; Treatment Outcome

The TAXUS Liberté Post Approval Study (TL-PAS) contributed patients treated with TAXUS Liberté paclitaxel-eluting stent and prasugrel to the Dual Antiplatelet Therapy Study (DAPT) that compared 12 and 30 months thienopyridine plus aspirin therapy after drug-eluting stents.. Outcomes for 2191 TL-PAS patients enrolled into DAPT were assessed. The DAPT coprimary composite end point (death, myocardial infarction [MI], or stroke) was lower with 30 compared with 12 months prasugrel treatment (3.7% versus 8.8%; hazard ratio [HR], 0.407; P<0.001). Rates of death and stroke were similar between groups, but MI was significantly reduced with prolonged prasugrel treatment (1.9% versus 7.1%; HR, 0.255; P<0.001). The DAPT coprimary end point, stent thrombosis, was also lower with longer therapy (0.2% versus 2.9%; HR, 0.063; P<0.001). MI related to stent thrombosis (0% versus 2.6%; P<0.001) and occurring spontaneously (1.9% versus 4.5%; HR, 0.407; P=0.007) were both reduced with prolonged prasugrel. MI rates increased within 90 days of prasugrel cessation after both 12 and 30 months treatment. Composite Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) moderate or severe bleeds were modestly increased (2.4% versus 1.7%; HR, 1.438; P=0.234) but severe bleeds were not more frequent (0.3% versus 0.5%; HR, 0.549; P=0.471) in the prolonged treatment group.. Prasugrel and aspirin continued for 30 months reduced ischemic events for the TAXUS Liberté paclitaxel-eluting stent patient subset from DAPT through reductions in MI and stent thrombosis. Withdrawal of prasugrel was followed by an increase in MI after both 12 and 30 months therapy. The optimal duration of dual antiplatelet therapy with prasugrel after TAXUS Liberté paclitaxel-eluting stent remains unknown, but appears to be >30 months.. http://www.clinicaltrials.gov. Unique identifier: NCT00997503.

Topics: Adult; Aged; Aged, 80 and over; Aspirin; Coronary Disease; Double-Blind Method; Drug Therapy, Combination; Drug-Eluting Stents; Female; Humans; Incidence; Internationality; Male; Middle Aged; Myocardial Infarction; Paclitaxel; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Pyridines; Thiophenes; Time Factors; Treatment Outcome

Prasugrel is being developed in Japan as an antiplatelet therapy for use during percutaneous coronary intervention (PCI). Up to 70% of Japanese patients with coronary artery disease undergo elective PCI. The PRASugrel For Japanese PatIenTs with Coronary Artery Diseases Undergoing Elective PCI (PRASFIT-Elective) study investigated the efficacy and safety of different prasugrel dosing regimens in Japanese patients undergoing elective PCI. METHODS AND RESULTS: A total of 742 patients scheduled for elective coronary artery stenting were enrolled. Patients were randomized to receive either prasugrel (20/3.75 mg, loading/maintenance dose) or clopidogrel (300/75 mg) in a double-blind manner. Endpoints, including cardiovascular events and bleeding, were assessed at weeks 24-48. The incidence rate of major cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal ischemic stroke) up to week 24 was 4.1% (15/370) and 6.7% (25/372) in the prasugrel and clopidogrel groups, respectively. Other incidence rates were: non-coronary artery bypass graft-related major bleeding, 0% and 2.2%; major/minor bleeding, 1.6% and 3.0%; and all bleeding events, 38.1% and 34.4% in the prasugrel and clopidogrel groups, respectively. The incidence rate of bleeding-related adverse events was similar in both groups, being 40.8% and 35.8% in the prasugrel and clopidogrel groups, respectively.. These results support the risk-benefit profile of an adjusted dosing regimen of prasugrel in Japanese patients undergoing PCI. Larger studies are required to confirm these findings.

Topics: Aged; Brain Ischemia; Clopidogrel; Combined Modality Therapy; Coronary Disease; Cytochrome P-450 CYP2C19; Double-Blind Method; Elective Surgical Procedures; Female; Follow-Up Studies; Gene Frequency; Hemorrhage; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Piperazines; Platelet Aggregation; Postoperative Complications; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Stents; Thiophenes; Ticlopidine

The goal of this study was to assess the offset of the antiplatelet effects of prasugrel and clopidogrel.. Guidelines recommend discontinuing clopidogrel at least 5 days and prasugrel at least 7 days before surgery. The pharmacodynamic basis for these recommendations is limited.. Aspirin-treated patients with coronary artery disease were randomly assigned to either prasugrel 10 mg or clopidogrel 75 mg daily for 7 days. Platelet reactivity was measured before study drug administration and for up to 12 days during washout. The primary endpoint was the cumulative proportion of patients returning to baseline reactivity after study drug discontinuation.. A total of 56 patients were randomized; 54 were eligible for analysis. Platelet reactivity was lower 24 h after the last dose of prasugrel compared with clopidogrel. After prasugrel, ≥75% of patients returned to baseline reactivity by washout day 7 compared with day 5 after clopidogrel. Recovery time was dependent on the level of platelet reactivity before study drug exposure and the initial degree of platelet inhibition after study drug discontinuation but not on treatment assignment.. Recovery time after thienopyridine discontinuation depends on the magnitude of on-treatment platelet inhibition, resulting, on average, in a more delayed recovery with prasugrel compared with clopidogrel. The offset of prasugrel was consistent with current guidelines regarding the recommended waiting period for surgery after discontinuation. (Prasugrel/Clopidogrel Maintenance Dose Washout Study; NCT01014624).

Topics: Adult; Aged; Aspirin; Blood Loss, Surgical; Blood Platelets; Clopidogrel; Confounding Factors, Epidemiologic; Coronary Disease; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Piperazines; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Prasugrel Hydrochloride; Thiophenes; Ticlopidine

Patients' responses to oral antiplatelet therapy are subject to variation. Bedside monitoring offers the opportunity to improve outcomes after coronary stenting by individualizing therapy.. We randomly assigned 2440 patients scheduled for coronary stenting at 38 centers to a strategy of platelet-function monitoring, with drug adjustment in patients who had a poor response to antiplatelet therapy, or to a conventional strategy without monitoring and drug adjustment. The primary end point was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization 1 year after stent implantation. For patients in the monitoring group, the VerifyNow P2Y12 and aspirin point-of-care assays were used in the catheterization laboratory before stent implantation and in the outpatient clinic 2 to 4 weeks later.. In the monitoring group, high platelet reactivity in patients taking clopidogrel (34.5% of patients) or aspirin (7.6%) led to the administration of an additional bolus of clopidogrel, prasugrel, or aspirin along with glycoprotein IIb/IIIa inhibitors during the procedure. The primary end point occurred in 34.6% of the patients in the monitoring group, as compared with 31.1% of those in the conventional-treatment group (hazard ratio, 1.13; 95% confidence interval [CI], 0.98 to 1.29; P=0.10). The main secondary end point, stent thrombosis or any urgent revascularization, occurred in 4.9% of the patients in the monitoring group and 4.6% of those in the conventional-treatment group (hazard ratio, 1.06; 95% CI, 0.74 to 1.52; P=0.77). The rate of major bleeding events did not differ significantly between groups.. This study showed no significant improvements in clinical outcomes with platelet-function monitoring and treatment adjustment for coronary stenting, as compared with standard antiplatelet therapy without monitoring. (Funded by Allies in Cardiovascular Trials Initiatives and Organized Networks and others; ARCTIC ClinicalTrials.gov number, NCT00827411.).

Topics: Aged; Aspirin; Clopidogrel; Coronary Disease; Coronary Thrombosis; Drug Monitoring; Female; Humans; Male; Middle Aged; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Point-of-Care Systems; Prasugrel Hydrochloride; Pyridines; Retreatment; Stents; Thiophenes; Ticlopidine

The metabolic pathways leading to the formation of prasugrel and clopidogrel active metabolites differ. We hypothesized that decreased CYP2C19 activity affects the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel.. Ninety-eight patients with coronary artery disease (CAD) taking either clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD were genotyped for variation in six CYP genes. Based on CYP genotype, patients were segregated into two groups: normal function (extensive) metabolizers (EM) and reduced function metabolizers (RM). Plasma active metabolite concentrations were measured at 30 min, 1, 2, 4, and 6 h post-LD and during the MD period on Day 2, Day 14, and Day 29 at 30 min, 1, 2, and 4 h. Vasodilator-stimulated phosphoprotein (VASP) and VerifyNow P2Y12 were measured predose, 2, and 24 +/- 4 h post-LD and predose during the MD period on Day 14 +/- 3 and Day 29 +/- 3. For clopidogrel, active metabolite exposure was significantly lower (P = 0.0015) and VASP platelet reactivity index (PRI, %) and VerifyNow P2Y(12) reaction unit (PRU) values were significantly higher (P < 0.05) in the CYP2C19 RM compared with the EM group. For prasugrel, there was no statistically significant difference in active metabolite exposure or pharmacodynamic response between CYP2C19 EM and RM. Variation in the other five genes demonstrated no statistically significant differences in pharmacokinetic or pharmacodynamic responses.. Variation in the gene encoding CYP2C19 in patients with stable CAD contributes to reduced exposure to clopidogrel's active metabolite and a corresponding reduction in P2Y(12) inhibition, but has no significant influence on the response to prasugrel.

Topics: Aryl Hydrocarbon Hydroxylases; Aspirin; Clopidogrel; Coronary Disease; Cytochrome P-450 CYP2C19; Drug Interactions; Female; Genetic Variation; Humans; Male; Middle Aged; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes; 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

Based on the preclinical and phase 1 studies, prasugrel, a novel platelet ADP P2Y12 receptor blocker, may be a more potent platelet inhibitor than clopidogrel. This study compared the antiplatelet properties of prasugrel in a small subset of patients enrolled in the JUMBO trial, and compared with historic clopidogrel treated controls.. Nine patients undergoing coronary stenting were randomised to one of three arms of prasugrel (40 mg loading, and 7.5 mg maintenance, n = 1; 60/10 mg, n = 4; or 60/15 mg, n = 2), or clopidogrel (300/75 mg, n = 2). Aspirin and GP IIb/IIIa inhibitors were permitted. Platelet activity was assessed at baseline, at 4, and 24 hours, and at 30 days after stent implantation in substudy participants, and compared with 124 historic controls who received clopidogrel. Independent of the loading, or maintenance dose, patients treated with prasugrel exhibited significantly more potent platelet inhibition as determined by ADP, and collagen induced aggregation, Ultegra Analyser, and surface expression of PECAM-1, GPIIb/IIIa antigen, and activity with PAC-1 antibody, GPIb, P-selectin, CD40-ligand, GP37, and thrombospondin receptor expression when compared with those treated with clopidogrel. There were no differences between antiplatelet agents with regard to vitronectin, LAMP-1, PAR-1 (intact and cleaved epitopes) thrombin receptor expression, or formation of platelet-monocyte microparticles. Expression of GPIIb antigen, vitronectin, and LAMP-3 receptor were not affected by both agents. Two patients treated with prasugrel 10 mg/daily exhibited complete inhibition of collagen induced aggregation at 30 days.. At the dosing regimens chosen in the JUMBO trial, it seems that prasugrel is a more potent antiplatelet agent than clopidogrel. Two episodes of profound platelet inhibition, which are not seen with clopidogrel, raise the possibility of higher bleeding risks especially during long term prasugrel use. Whether stronger platelet inhibition will yield better clinical outcomes and/or increased bleeding remains to be determined in an ongoing comparative phase 3 superiority trial (TRITON).

Topics: Clopidogrel; Coronary Disease; Female; Flow Cytometry; Humans; Male; Middle Aged; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Stents; Thiophenes; 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

Patients with acute coronary syndrome (ACS) and previous cardiovascular disease (CVD) (stroke, peripheral arterial disease [PAD] or coronary artery disease [CAD]) are at high risk of serious events and mortality. Current clinical guidelines recommend new antiplatelet drugs (NADs) for high cardiovascular risk patients with ACS; however, these drugs are underused in different scenarios.. This study included 1717 ACS patients from 3 tertiary hospitals. Of them, 641 (37.33%) suffered from previous CVD: 149 patients with stroke, 154 patients with PAD and 541 patients with CAD. Bleeding, mortality and major adverse cardiac events (MACE) at 1 year of follow-up after hospital discharge were analyzed.. NADs administration during hospital stay and at discharge was less frequent in patients with previous CVDs (P<0.001, for both). Cox analysis in this cohort of patients showed that clopidogrel prescription at discharge was independently associated with MACEs (HR: 1.59 [95% CI: 1.03-2.45]; P=0.036) and with death (HR: 1.99 [95% CI: 1.00-3.98]; P=0.049) in multivariate analysis. More specifically, when ticagrelor prescription at discharge was compared with clopidogrel, a significant death reduction was found in both, the univariate and the multivariate Cox analysis (HR: 4.54 [95% CI: 2.26-9.13]; P<0.001 and HR: 2.61 [95% CI: 1.16-5.90]; P=0.021, respectively).. New antiplatelet drugs, especially ticagrelor, showed lower rates of mortality in patients with CVD without differences for bleeding. Despite the recommendations of current clinical guidelines for high risk patients with ACS, the use of NADs is very low in "real-life" patients with previous CVD.

Topics: Acute Coronary Syndrome; Aftercare; Clopidogrel; Comorbidity; Coronary Disease; Drug Utilization; Female; Follow-Up Studies; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Metabolic Syndrome; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Proportional Hazards Models; Prospective Studies; Smoking; Spain; Stroke; Tertiary Care Centers; Ticagrelor

A single-center observational study was conducted in 1193 patients who underwent percutaneous coronary intervention and received DAPT after implementation of an algorithm that recommends. Implementing

Topics: Aged; Clinical Decision-Making; Clopidogrel; Coronary Disease; Cytochrome P-450 CYP2C19; Feasibility Studies; Female; Humans; Male; Middle Aged; North Carolina; Patient Selection; Percutaneous Coronary Intervention; Pharmacogenomic Testing; Pharmacogenomic Variants; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Predictive Value of Tests; Reproducibility of Results; Retrospective Studies; Risk Factors; Stents; Ticagrelor; Treatment Outcome

Topics: Aspirin; Clopidogrel; Coronary Disease; Cost Savings; Desensitization, Immunologic; Drug Hypersensitivity; Drug Substitution; Humans; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Salicylates; Ticlopidine

Topics: Aspirin; Coronary Disease; Drug-Eluting Stents; Female; Humans; Male; Paclitaxel; Piperazines; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Thiophenes

Topics: Coronary Disease; Female; Humans; Male; Percutaneous Coronary Intervention; Piperazines; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Thiophenes

Topics: Adenosine; Aftercare; Angioplasty, Balloon, Coronary; Coronary Disease; Follow-Up Studies; Humans; Myocardial Revascularization; Percutaneous Coronary Intervention; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Recurrence; Retreatment; Risk Factors; Stents; Survival Rate; Thiophenes; Ticagrelor

Topics: Aspirin; Clinical Trials as Topic; Clopidogrel; Coronary Disease; Drug Therapy, Combination; Drug-Eluting Stents; Female; Humans; Male; Multicenter Studies as Topic; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes; 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