Effect of the novel direct factor Xa inhibitor DX-9065a on thrombin generation and inhibition among patients with stable atherosclerotic coronary artery disease.
BACKGROUND
Thrombin, a pluripotential effector enzyme with prothrombotic, proinflammatory, and mitogenic properties, plays a pivotal role in the pathobiology and clinical expression of atherothrombotic coronary artery disease. Existing anticoagulant drugs have not been shown to attenuate thrombin generation or activity consistently. We sought to investigate the effect of DX-9065a on thrombin generation and inhibition in patients with stable CAD. DX-9065a is a small-molecule, synthetic, direct inhibitor of factor Xa.


METHODS
Peripheral venous blood samples were collected serially during and after administration of either placebo or 1 of 4 weight-adjusted regimens of DX-9065a, in 73 patients with stable CAD participating in the XaNADU-1B study.


CONCLUSIONS
At baseline, the median (25th, 75th) prothrombin activation fragment 1.2 (F1.2) level was 2.56 (2.05, 3.20) nmol/L, and the median d-dimer level was 0.26 (0.19, 0.38) microg FEU/L. There were significant relationships between measured plasma DX-9065a concentrations and both F1.2 (4.9% decrease for each doubling of DX-9065a) (P<0.0001) and d-dimer (5.5% decrease for each doubling of DX-9065a) (P=0.001). F1.2 was suppressed (below baseline) at 96 h after administration of DX-9065a. Coronary thrombotic events did not occur during or after study drug administration. DX-9065a, the first in a class of small-molecule, direct, selective and reversible factor Xa inhibitors, reduces thrombin generation and fibrin formation among patients with stable CAD. The effect is concentration-dependent and persists for at least 96 h following drug cessation, without biochemical or clinical evidence of rebound.
Becker
Richard C
RC
Duke Cardiovascular Thrombosis Center, Duke University School of Medicine, Durham, NC 27710 USA.
Alexander
John H
JH
Dyke
Christopher
C
Huang
Yao
Y
Saint-Jacques
Henock
H
Hasselblad
Vic
V
Harrington
Robert A
RA
Bovill
Edwin G
EG
D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage; D000990:Antithrombin III / Q000008:administration & dosage*; D003324:Coronary Artery Disease / Q000097:blood* / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000008:administration & dosage*; D011422:Propionates / Q000008:administration & dosage*; D013917:Thrombin / Q000032:analysis* / Q000037:antagonists & inhibitors*
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000925:Anticoagulants; D009281:Naphthalenes; D011422:Propionates; D000990:Antithrombin III; D013917:Thrombin