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 microg/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 microg/kg were comparable to that with placebo (6.7%), whereas an incidence of 26.9% was observed at the 10.0 microg/kg dose level (p < 0.01). Major bleedings occurred in the 5.0 microg/kg (n = 3) and 7.5 microg/kg (n = 1) dose groups. The three patients in the 5.0 microg/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 (F(1+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 F(1+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 microg/kg, in combination with aspirin, clopidogrel, and unfractionated heparin appears to be a safe and effective strategy to prevent thrombin generation during coronary angioplasty.