A Randomized, Double-Blind, Active-Controlled Phase 2 Trial to Evaluate a Novel Selective and Reversible Intravenous and Oral P2Y(12) Inhibitor Elinogrel Versus Clopidogrel in Patients Undergoing Nonurgent Percutaneous Coronary Intervention The INNOVATE-PCI Trial
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.
"Moreover, more frequent hemorrhages requiring medical assistance were present within 24 h to 120 days in patients treated with elinogrel at the dose of 150 mg. It needs to be added that the research did not have appropriate statistical properties to assess ischemic endpoints . The implications of these results require further studies in the third stage. "
[Show abstract][Hide abstract] ABSTRACT: Antiplatelet drugs play a crucial role in the treatment of patients with myocardial infarction, particularly in association with percutaneous coronary intervention. Their main advantage is the reduction of adverse ischemic incidents and the major disadvantage is the increase in the frequency of hemorrhages. Thus, the choice of appropriate drug depends on the right risk assessment of the development of these complications in individual patients. The aim of this article is to provide an update of antiplatelet therapy in emergency myocardial infarction treatment. Currently, the most important role in the process of platelet inhibition is played by ADP P2Y12 blockers: clopidogrel, prasugrel and ticagrelor. Clopidogrel and prasugrel belong to thienopyridines, and ticagrelor, a drug of irreversible action, is an analogue of adenosine triphosphate. By 2011 clopidogrel, alongside aspirin, had the highest recommendations of world cardiology associations for acute coronary syndrome treatment. The position on clopidogrel was changed following the publication of European Society of Cardiology guidelines for STEMI in 2012 which advocate the administration of acetylsalicylic acid (ASA) and ADP receptor blocker (in combination with ASA). It needs to be stressed that prasugrel and ticagrelor received class IB recommendation, while clopidogrel received only IC. However, the most recent studies aimed at introducing a new generation of antiplatelet drugs of high efficacy in prevention of ischemic incidents and of reversible action: cangrelor and elinogrel, which raise hopes for better prognosis for myocardial infarction patients.
Postepy w Kardiologii Interwencyjnej / Advances in Interventional Cardiology 03/2014; 10(1):32-39. DOI:10.5114/pwki.2014.41466 · 0.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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