Abstract 9771: Reg1, a Novel RNA-Aptamer Direct Factor IXa-inhibitor (pegnivacogin) Reduces Platelet Activation in Healthy Volunteers and Residual Platelet Aggregation in Patients with ACS. A Radar Substudy
Background and Rationale: Residual platelet reactivity is a predictor of cardiovascular adverse events in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary interventions (PCI). In addition to patient factors and antiplatelet therapy, the choice of anticoagulant determines the risk for periprocedural ischemic and bleeding events. The ideal anticoagulant would demonstrate a fast onset, effective anticoagulation, and controlable reversibility. REG1 consisting of pegnivacogin, a RNA-aptamer direct factor IXa inhibitor, and anivamersen, its specific, and titratable active control agent meets these requirements. We examined whether inhibition of factor IXa with pegnivacogin affects platelet reactivity in vitro and in vivo in healthy volunteers and in a subset of patients with ACS undergoing PCI from the phase IIb RADAR trial (NCT00932100).
Methods and Results: For the in vitro study, blood from healthy volunteers was spiked with pegnivacogin (50µg/ml) and ADP-induced platelet activation was measured by flow cytometry (expression of CD62P and PAC-1 binding). Platelet aggregation was assessed by light transmission aggregometry (LTA). For the in vivo measurements, LTA was done with blood from patients with ACS enrolled in the RADAR trial. Blood samples were taken before and 20 minutes after the administration of pegnivacogin. All patients were loaded with clopidogrel (600mg) and aspirin (>325mg). In vitro pegnivacogin significantly reduced maximum ADP-induced CD62P-expression (100% vs 89.8+/- 12.1%, p=0.0035) and PAC-1 binding (100% vs 83+/-18.5%, p=0.0006). Furthermore maximum platelet aggregation was reduced by 26.3+/-16.4% (p=0.0031). In patients with ACS residual platelet aggregation (1µM ADP) was reduced from 33.3+/-4% to 14.7+/-8.1% (n=4, p=0.005) 20 minutes after intravenous pegnivacogin (1mg/kg).
Conclusion: The novel IXa inhibitor pegnivacogin decreases ADP-induced platelet activation and aggregation in vitro and in vivo. In addition to its effect as an anticoagulant, REG1 may provide a means to overcome residual platelet reactivity in patients with ACS undergoing PCI, this may contribute to clinical outcomes and should be studied in appropriately sized phase 3 clinical trials.
- © 2011 by American Heart Association, Inc.