Recombinant nematode anticoagulant protein c2, an inhibitor of the tissue factor/factor VIIa complex, in patients undergoing elective coronary angioplasty

Objectives We investigated the safety and pharmacodynamics of escalating doses of recombinant nematode anticoagulant protein c2 (rNAPc2) in patients undergoing elective coronary angioplasty. Background Recombinant NAPc2 is a potent inhibitor of the tissue factor/factor VIIa complex, which has the potential to reduce the risk of thrombotic complications in coronary artery disease. Methods In a randomized, double-blinded, dose-escalation, multicenter trial, 154 patients received placebo or rNAPc2 at doses of 3.5, 5.0, 7.5, and 10.0 μg/kg body weight as a single subcutaneous administration 2 to 6 h before angioplasty. All patients received aspirin, unfractionated heparin during angioplasty, and clopidogrel in case of stent implantation. Results Minor bleeding rates for the doses 3.5 to 7.5 μg/kg were comparable to that with placebo (6.7%), whereas an incidence of 26.9% was observed at the 10.0-μg/kg dose level (p < 0.01). Major bleedings occurred in the 5.0-μg/kg (n = 3) and 7.5-μg/kg (n = 1) dose groups. The three patients in the 5.0-μg/kg dose group also received a glycoprotein IIb/IIIa receptor inhibitor at the moment of major bleeding. Systemic thrombin generation, as measured by prothrombin fragment 1+2 (F1+2), was suppressed in all rNAPc2 dose groups to levels below pretreatment values for at least 36 h. In the placebo group, a distinct increase of F1+2 levels was observed following cessation of heparin. Conclusions Inhibition of the tissue factor/factor VIIa complex with rNAPc2, at doses up to 7.5 μg/kg, in combination with aspirin, clopidogrel, and unfractionated heparin appears to be a safe and effective strategy to prevent thrombin generation during coronary angioplasty.