elinogrel and Hemorrhage

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

P2Y12, one of the two platelet receptors for adenosine diphosphate (ADP), plays a central role in platelet function. Defects of P2Y12 should be suspected when ADP, even at high concentrations (≥10 µM), is unable to induce full, irreversible platelet aggregation. Patients with congenital P2Y12 defects display a mild-to-moderate bleeding diathesis of variable severity, characterised by mucocutaneous bleeding and excessive post-surgical and post-traumatic blood loss. Drugs that inhibit P2Y12 are potent antithrombotic drugs, attesting the central role played by P2Y12 in platelet thrombus formation. Clopidogrel, the most widely used drug that inhibits P2Y12, is effective both in monotherapy and in combination with acetylsalicylic acid (ASA). Its most important drawback is the inability to inhibit adequately P2Y12-dependent platelet function in about 1/3 of patients, at the recommended therapeutic doses. The incidence of bleeding events is similar in ASA-treated and clopidogrel-treated patients; however, the combination of ASA and clopidogrel causes more bleeding than each drug in monotherapy. Compared to clopidogrel, new drugs inhibiting P2Y12, such as prasugrel and ticagrelor, decrease the risk of cardiovascular events and increase the risk of bleeding complications, because they adequately inhibit P2Y12-dependent platelet function in the vast majority of treated patients.

Topics: Adenosine; Adenosine Diphosphate; Adenosine Monophosphate; Animals; Clinical Trials, Phase III as Topic; Clopidogrel; Hemorrhage; Humans; Piperazines; Platelet Activation; Prasugrel Hydrochloride; Quinazolinones; Receptors, Purinergic P2Y12; Sulfonamides; Thiophenes; Ticagrelor; Ticlopidine

We evaluated the safety, efficacy, and tolerability of elinogrel, a competitive, reversible intravenous and oral P2Y(12) inhibitor that does not require metabolic activation, in patients undergoing nonurgent percutaneous coronary intervention.. In a randomized, double-blind, dose-ranging phase 2b trial, 652 patients received either 300 or 600 mg of clopidogrel pre-percutaneous coronary intervention followed by 75 mg daily or 80 or 120 mg of IV elinogrel followed by 50, 100, or 150 mg oral elinogrel twice daily. Numerous exploratory safety and efficacy end points were assessed and, as such, had no prespecified primary end point, and the study was not powered to conclusively evaluate its objectives. Thrombolysis in myocardial infarction combined bleeding was increased with elinogrel (hazard ratio, 1.98; 95% confidence interval, 1.10 to 3.57), related largely to increased bleeding requiring medical attention (elinogrel 47/408 [11.5%] versus clopidogrel 13/208 [6.3%]) and occurring primarily at the percutaneous coronary intervention access site. Efficacy end points and postprocedure cardiac enzyme were similar, but there was a nonsignificant higher frequency of periprocedural myocardial infarctions in the elinogrel arms (OR, 1.59; 95% confidence interval, 0.79 to 3.48). There was an increased incidence of dyspnea (elinogrel 50/408 [12.3%] versus clopidogrel 8/208 [3.8%]) and transaminase elevation (alanine transferase/aspartate transferase >3× the upper limit of normal; elinogrel 18/408 [4.4%] versus clopidogrel 2/208 [1.0%]) in the elinogrel arms, but there were no cases of heart block, bradycardia, hypotension, or liver failure.. In patients undergoing nonurgent percutaneous coronary intervention and in comparison with clopidogrel, intravenous and oral elinogrel therapy did not significantly increase thrombolysis in myocardial infarction major or minor bleeding, although bleeding requiring medical attention was more common. The significance of these findings will need to be more definitively determined in future Phase 3 studies.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00751231.

Topics: Administration, Oral; Angioplasty, Balloon, Coronary; Canada; Clopidogrel; Disease-Free Survival; Double-Blind Method; Drug Administration Schedule; Europe; Female; Heart Diseases; Hemorrhage; Humans; Injections, Intravenous; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Platelet Aggregation; Platelet Aggregation Inhibitors; Proportional Hazards Models; Purinergic P2Y Receptor Antagonists; Quinazolinones; Receptors, Purinergic P2Y12; Risk Assessment; Risk Factors; Stroke; Sulfonamides; Thrombosis; Ticlopidine; Time Factors; Treatment Outcome; United States

Clinical studies with clopidogrel or prasugrel show that although increased inhibition of P2Y(12) and platelet function improves efficacy, bleeding is also increased. Other preclinical and clinical studies have suggested a greater therapeutic index (TI) with reversible inhibitors and disproportionate effects of thienopyridines on bleeding at high doses. We used multiple in vivo (FeCl(3)-induced arterial thrombosis in mesenteric arteries, blood loss after tail transsection, and platelet deposition and wound closure time in a micropuncture model in mesenteric veins) and ex vivo (light transmittance aggregometry, prothrombin time, and activated partial thromboplastin time) mouse models to 1) compare the TI of clopidogrel, prasugrel, and elinogrel, a reversible, competitive antagonist, with that in P2Y(12)(-/-) mice and 2) determine whether the bleeding consequences of the thienopyridines are attributed only to the inhibition of P2Y(12). Data indicated greater (elinogrel) and decreased (thienopyridines) TI compared with that in P2Y(12)(-/-) mice. The impaired TI associated with the thienopyridines was not attributed to non-P2Y(12) activities on platelet function or coagulation but was related to a direct effect at the vessel wall (inhibition of vascular tone). Further analysis showed that the prasugrel off-target effect was dose- and time-dependent and of a reversible nature. In conclusion, the TI of thienopyridines in the mouse may be decreased by P2Y(12)-independent off-target effects at the vessel wall, whereas that of elinogrel may be enhanced by the reversible, competitive nature of the antiplatelet agent.

Topics: Animals; Dose-Response Relationship, Drug; Drug Delivery Systems; Endothelium, Vascular; Hemorrhage; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Quinazolinones; Receptors, Purinergic P2Y12; Sulfonamides; Thienopyridines; Thrombosis