elinogrel and Heart-Diseases

Elinogrel is the only selective, competitive and reversible platelet P2Y(12) inhibitor available in both intravenous (IV) and oral formulations.. This substudy of the Intravenous and Oral Administration of Elinogrel to Evaluate Tolerability and Efficacy in Nonurgent Percutaneous Coronary Intervention patients (INNOVATE-PCI) trial evaluated the pharmacokinetic and pharmacodynamic effects of two dosing regimens of IV followed by oral elinogrel (120 mg IV plus 100 mg oral twice daily; 120 mg IV plus 150 mg oral twice daily) versus standard clopidogrel therapy (300-600 mg oral loading dose plus 75 mg oral maintenance dose) in 56 patients undergoing nonurgent PCI. At time of randomization, 71.4% (40/56) of patients were using maintenance clopidogrel therapy. In the acute phase, an IV bolus of elinogrel achieved more rapid and potent antiplatelet effects compared with clopidogrel, which were sustained during the transition from the IV to the oral formulation in the first 24 hours of the peri-PCI period. During chronic therapy, elinogrel achieved similar levels of platelet reactivity compared with clopidogrel before the next oral dose and, although platelet reactivity was lower with elinogrel up to 6 hours after daily oral maintenance dosing, these differences were not statistically significant. These pharmacodynamic effects matched the pharmacokinetic profile of elinogrel. There were no differences in pharmacodynamic and pharmacokinetic effects between the two elinogrel dosing regimens.. Compared with clopidogrel, the combination of IV and oral elinogrel achieves more rapid and enhanced antiplatelet effects that were sustained through the transition to oral elinogrel in the peri-PCI period, but these were not significant during chronic dosing in this pilot investigation.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00751231.

Topics: Administration, Oral; Angioplasty, Balloon, Coronary; Canada; Clopidogrel; Double-Blind Method; Drug Administration Schedule; Europe; Female; Heart Diseases; Humans; Injections, Intravenous; Male; Middle Aged; Models, Statistical; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Purinergic P2Y Receptor Antagonists; Quinazolinones; Receptors, Purinergic P2Y12; Sulfonamides; Ticlopidine; Treatment Outcome; United States

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

Topics: Angioplasty, Balloon, Coronary; Clopidogrel; Female; Heart Diseases; Humans; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Quinazolinones; Receptors, Purinergic P2Y12; Sulfonamides; Ticlopidine