elinogrel and Acute-Coronary-Syndrome

New P2Y12 inhibitors can be classified as oral (prasugrel and ticagrelor) and intravenous drugs (cangrelor and elinogrel). These P2Y12 inhibitors might be superior to clopidogrel for reducing ischemic events in patients with coronary artery disease (CAD). We performed a meta-analysis of randomized trials that compared new oral or intravenous P2Y12 inhibitors with clopidogrel to determine their efficacy and safety in patients.. Twelve randomized, placebo-controlled studies and two subgroup analyses of included studies on ST-segment elevation myocardial infarction (STEMI) were included. The database consisted of 82,784 patients, with 43,875 (53%) on new oral P2Y12 inhibitors and 38909 (47%) on intravenous P2Y12 inhibitors compared with clopidogrel. The primary efficacy endpoint was major adverse cardiac events (MACEs). The primary safety endpoint was thrombolysis in myocardial infarction (TIMI) major bleeding. New oral P2Y12 inhibitors significantly decreased MACEs (odds ratio: 0.85, p<0.0001 for the whole cohort; OR: 0.77, p=0.04 for STEMI) and all-cause death (OR: 0.88, p=0.04 for the whole cohort; OR: 0.77, p=0.01 for STEMI). Among new intravenous P2Y12 inhibitors, only cangrelor significantly decreased the risk of MACEs. An increase in TIMI major bleeding was observed only by prasugrel among the new P2Y12 inhibitors.. New oral P2Y12 inhibitors reduce ischemic events, but there is no obvious increase in major bleeding in patients with CAD, and the risk/benefit ratio is particularly favorable for STEMI patients. Moreover, only cangrelor is beneficial for ischemic events in patients on new intravenous P2Y12 inhibitors.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Administration, Oral; Clopidogrel; Coronary Artery Disease; Coronary Restenosis; Fibrinolytic Agents; Hemorrhage; Humans; Injections, Intravenous; Multicenter Studies as Topic; Myocardial Infarction; Piperazines; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Quinazolinones; Randomized Controlled Trials as Topic; Stents; Stroke; Sulfonamides; Thiophenes; Thrombolytic Therapy; Ticagrelor; Ticlopidine

The activation and aggregation of platelets at sites of vascular injury or near to implanted stent are pivotal in the development of thrombotic events during and after an acute coronary syndrome (ACS) or a percutaneous coronary intervention (PCI). For that reason, an exclusively oral dual antiplatelet treatment regimen with platelet P2Y12 receptor antagonists in addition to the cyclooxygenase inhibitor aspirin has become the cornerstone of treatment in that contest. However, every trial underlines the same problem: if maximizing antiplatelet therapy significantly attenuates ischemic events in patients with coronary artery disease, on the other side it may also increase bleeding phenomena. These limitations have prompted a search for novel antiplatelet agents with a more favorable risk-benefit ratio. Moreover, an early onset of action is desirable during PCI and an early offset after bleeding events. Two novel antiplatelet agents, Cangrelor and Elinogrel, are available in intravenous form (Elinogrel also in oral form) and expand this context. Recent trials have tested them against Clopidogrel regarding efficacy and safety outcomes.This review aimed at providing an overview on intravenous emerging compounds and recent patents in the setting of ACS and PCI.

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Hemorrhage; Humans; Patents as Topic; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Quinazolinones; Sulfonamides

Admissions to emergency care centres with acute coronary syndromes remain one of the principal burdens on healthcare systems in the Western world. Early pharmacological treatment in these patients is crucial, lessening the impact on both morbidity and mortality, with the cornerstone of management being antiplatelet agents. While aspirin and clopidogrel have been the drugs of choice for nearly a decade, an array of newer, more potent antiplatelet agents are now available or in late stage development. Data are rapidly gathering suggesting these agents have superior anti-ischaemic properties, improving patient outcomes, but that for some agents increased vigilance and appropriate patient selection may be necessary to guard against bleeding complications. In this review, the authors aim to deliver an overview of the changing field of antiplatelet therapy and provide information about the relative risks and benefits of these newer agents, many of which will be entering widespread clinical use imminently.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Aspirin; Clopidogrel; Emergency Treatment; Female; Humans; Male; Patient Selection; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Quinazolinones; Sulfonamides; Thiophenes; Ticagrelor; Ticlopidine; Treatment Outcome

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

Dual antiplatelet therapy with aspirin and clopidogrel is a well-established standard of care for patients with acute coronary syndromes. Whether there are other drug strategies or therapies that will achieve fewer ischemic events, and at the same time be associated with fewer bleeding complications, is a question recurrently asked. Finding the appropriate pharmacologic calibration of antiplatelet potency and applying such a pharmacodynamic effect to all patients has only been partially successful. The shadow of this one-size-fits-all dilemma is now being recast with the arrival of newer antiplatelet agents, which are attempting to decouple antithrombotic potency from bleeding liability. Novel antiplatelet agents that act faster and have more consistent pharmacokinetics and higher potency are steadily emerging. Additionally, newer agents that target unique sites, such as the thrombin receptor on platelets, are being studied in large-scale clinical trials. Each of these new agents has the potential to extend net clinical benefits beyond those provided by aspirin and clopidogrel.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Aspirin; Cilostazol; Clopidogrel; Drug Therapy, Combination; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Quinazolinones; Receptors, Purinergic P2Y12; Sulfonamides; Tetrazoles; Thiophenes; Ticagrelor; Ticlopidine

P2Y purinergic receptor subtypes are expressed on the surface of platelets and are vitally important for platelet function. Elinogrel (PRT-060128), a novel, direct-acting and reversible platelet P2Y12 receptor (P2Y12R) antagonist, is being developed by Portola Pharmaceuticals Inc and Novartis AG for the intravenous and oral treatment of acute coronary syndrome and prevention of secondary thrombotic events. In phase I clinical trials, elinogrel demonstrated a rapid and potent inhibition of ADP-mediated platelet response, even in patients with coronary artery disease who were deemed non-responsive to clopidogrel, the current standard-of-care therapy. The pharmacodynamic effects of single-dose elinogrel were completely reversed within 24 h of administration and elinogrel was well tolerated with no significant adverse events reported. The results of a phase II clinical trial in patients undergoing non-urgent percutaneous coronary intervention are highly anticipated because elinogrel will be the first P2Y12R antagonist to be available in both intravenous and oral formulations to facilitate a smooth transition from short- to long-term treatment. Unlike the currently available P2Y12R antagonists, which require hepatic transformation to an active metabolite and elicit irreversible effects on platelets, elinogrel directly inhibits the P2Y12R with a fast onset and offset and is therefore a promising candidate for cardiovascular protection.

Topics: Acute Coronary Syndrome; Animals; Clinical Trials as Topic; Humans; Purinergic P2 Receptor Antagonists; Quinazolinones; Receptors, Purinergic P2Y12; Sulfonamides; Thrombosis

The purpose of this study was to perform a meta-analysis of randomized trials that compare new P2Y(12) inhibitors with clopidogrel to determine whether they improve clinical outcomes after percutaneous intervention (PCI).. Ticlopidine/clopidogrel prevents major adverse cardiac events after PCI, but no trials have shown an effect on mortality. New P2Y(12) inhibitors are more potent and evaluated in PCI. Whether they decrease mortality after PCI compared with clopidogrel is unknown.. MEDLINE and Cochrane Controlled Trials Register databases were searched from January 1980 through January 2010. Randomized, placebo-controlled trials that compared new P2Y(12) antagonists with clopidogrel in PCI were selected. Data from 8 studies were evaluated and analyses performed for all randomized patients, PCI patients (any PCI), and PCI for ST-segment elevation myocardial infarction (STEMI) patients. All-cause mortality was the primary efficacy end point. Thrombolysis In Myocardial Infarction major bleeding was the primary safety end point.. A total of 48,599 patients were included with 94% of patients with acute coronary syndrome and 84% of patients undergoing PCI. New P2Y(12) inhibitors significantly decreased death (odds ratio [OR]: 0.83, 95% confidence interval [CI]: 0.75 to 0.92, p < 0.001 for the whole cohort; OR: 0.85, 95% CI: 0.75 to 0.96, p = 0.008 for any PCI; and OR: 0.78, 95% CI: 0.66 to 0.92, p = 0.003 for PCI for STEMI). In PCI patients, new P2Y(12) inhibitors also significantly decreased major adverse cardiac events by 18% (p < 0.001) and stent thrombosis by 40% (p < 0.001). Although there was an increase in Thrombolysis In Myocardial Infarction major bleeding for any PCI (OR: 1.23, 95% CI: 1.04 to 1.46, p = 0.01), no difference was observed in PCI for STEMI (OR: 0.98, 95% CI: 0.85 to 1.13, p = 0.76), with similar outcomes in primary PCI for STEMI. Results were confirmed in sensitivity analyses that removed the largest study.. New P2Y(12) inhibitors decrease mortality after PCI compared with clopidogrel. The risk/benefit ratio is particularly favorable in PCI for STEMI patients.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Clopidogrel; Humans; Postoperative Complications; Purinergic P2 Receptor Antagonists; Quinazolinones; Randomized Controlled Trials as Topic; Receptors, Purinergic P2Y12; Sulfonamides; Ticlopidine

Despite the proven efficacy of dual antiplatelet therapy with aspirin and one of the first-generation P2Y(12) antagonists (clopidogrel, prasugrel) in patients with atherothrombotic disease, residual ischemic risk remains substantial, and bleeding rates are increased. Incomplete protection against ischemic events can be attributed to the fact that these therapies each target a single platelet activation pathway, allowing continued platelet activation via other pathways, including the protease-activated receptor-1 (PAR-1) pathway stimulated by thrombin. Increased bleeding with dual antiplatelet therapy can be attributed to blockade of the thromboxane A(2) (by aspirin) and adenosine diphosphate (by P2Y(12) antagonist) platelet activation pathways that are essential to hemostasis. The second-generation P2Y(12) inhibitor ticagrelor plus aspirin demonstrated superior ischemic outcomes, including reduction in total mortality, versus clopidogrel plus aspirin, but event rates remain high, and major bleeding not related to coronary artery bypass grafting is increased. The novel P2Y(12) antagonist elinogrel, available in intravenous and oral formulations, may have a more favorable benefit-to-risk profile than existing agents in this class because of reversible and competitive binding to the P2Y(12) receptor. Inhibition of PAR-1 is an attractive, novel approach in antiplatelet therapy because it may provide incremental ischemic protection without increasing bleeding. The PAR-1 antagonist vorapaxar (SCH 530348) has been associated with favorable efficacy and safety in phase 2 trials. Two phase 3 trials are evaluating the efficacy and safety of vorapaxar in patients presenting with non-ST-segment elevation acute coronary syndromes and in patients with documented atherothrombotic disease.

Topics: Acute Coronary Syndrome; Adenosine; Angioplasty, Balloon, Coronary; Aspirin; Clopidogrel; Coronary Artery Disease; Coronary Thrombosis; Drug Therapy, Combination; Humans; Lactones; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Pyridines; Quinazolinones; Randomized Controlled Trials as Topic; Receptor, PAR-1; Sulfonamides; Ticagrelor; Ticlopidine