elinogrel and Thrombosis

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

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

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

The antiplatelet therapy with aspirin and the ADP-receptor blocker clopidogrel is currently the standard medication after coronary intervention or after acute coronary syndrome to prevent recurrent ischemic events and reduce mortality. However, high interindividual response variability to antiplatelet treatment is described in up to 44% of treated patients. A poor response to clopidogrel is caused by multifactorial mechanisms. Individual risk assessment including platelet function testing (PFT) can help to identify high risk patients, although recent randomized trials to investigate effects of PFT-guided therapy have failed to detect an impact on prognostic outcome. Poor response to standard antiplatelet agents can be overcome by switching to alternate substances. Elinogrel is a novel competitive, reversible ADP-receptor antagonist available in oral and intravenous formulation. Additional treatment with elinogrel showed advantages over clopidogrel, including more rapid, less variable, and more complete inhibition of platelet function without significantly increased bleeding complications. This review gives an overview over the investigational drug elinogrel for use in a personalized antiplatelet approach.

Topics: Administration, Oral; Evidence-Based Medicine; Fibrinolytic Agents; Humans; Injections, Intravenous; Platelet Aggregation Inhibitors; Precision Medicine; Purinergic P2Y Receptor Antagonists; Quinazolinones; Sulfonamides; Thrombosis; Treatment Outcome

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

It is known that hepatic metabolism limits the antiaggregatory activity of clopidogrel and, as a consequence, its clinical benefits. In this study, we investigated whether other factors exist that could account for clopidogrel's suboptimal antithrombotic activity. Using an in vivo murine FeCl(3) thrombosis model coupled with intravital microscopy, we found that at equivalent, maximal levels of inhibition of ADP-induced platelet aggregation, clopidogrel (50 mg/kg p.o.) failed to reproduce the phenotype associated with P2Y(12) deficiency. However, elinogrel (60 mg/kg p.o.), a direct-acting reversible P2Y(12) antagonist, achieved maximal levels of inhibition in vivo, and its administration (1 mg/kg i.v.) abolished residual thrombosis associated with clopidogrel dosing. Because elinogrel is constantly present in the plasma, whereas the active metabolite of clopidogrel exists for ∼2 h, we evaluated whether an intracellular pool of P2Y(12) exists that would be inaccessible to clopidogrel and contribute to its limited antithrombotic activity. Using saturation [(3)H]2-(methylthio)ADP ([(3)H]2MeSADP) binding studies, we first demonstrated that platelet stimulation with thrombin and convulxin (mouse) and thrombin receptor activating peptide (TRAP) (human) significantly increased surface expression of P2Y(12) relative to that of resting platelets. We next found that clopidogrel dose-dependently inhibited ADP-induced aggregation, signaling (cAMP), and surface P2Y(12) on resting mouse platelets, achieving complete inhibition at the highest dose (50 mg/kg), but failed to block this inducible pool. Thus, an inducible pool of P2Y(12) exists on platelets that can be exposed upon platelet activation by strong agonists. This inducible pool is not blocked completely by clopidogrel, contributes to thrombosis in vivo, and can be blocked by elinogrel.

Topics: Animals; Clopidogrel; Cyclic AMP; Fibrinolytic Agents; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; P-Selectin; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Agonists; Purinergic P2Y Receptor Antagonists; Quinazolinones; Radioligand Assay; Receptors, Purinergic P2Y12; Sulfonamides; Thrombosis; Ticlopidine