A novel synthetic inhibitor of factor Xa decreases early reocclusion and improves 24-h patency after coronary fibrinolysis in dogs.
Inhibition of factor Xa (FXa) attenuates thrombus progression. This study was designed to determine whether a novel, synthetic inhibitor of FXa (ZK-807834, molecular mass 527 Da, K(i) = 0.11 nM) administered during and briefly after pharmacologic coronary fibrinolysis increases 24-h patency. Either ZK-807834 (< or = 1.6 mg/kg, n = 10; 6.5 mg/kg, n = 8; or 13 mg/kg, n = 7); a peptide inhibitor of FXa, recombinant tick anticoagulant peptide (rTAP, 13.6 mg/kg, n = 7); heparin (150 U/kg bolus and 50 U/kg/h infusion) and aspirin (5 mg/kg) (n = 7); or saline as a control (n = 13) were administered i.v. over 135 min in conscious dogs after thrombotic occlusion induced by electrical injury to a coronary artery. Fibrinolysis was induced with recombinant human tissue-type plasminogen activator (1.0 mg/kg i.v. over 1 h), and patency was monitored continuously for 24 h with an implanted Doppler probe. Reocclusion occurred in all control and heparin/aspirin-treated dogs within 1 h after fibrinolysis. High dose ZK-807834 prevented reocclusion in five of six dogs and delayed reocclusion in the other dog (186 min after recanalization, p = 0.0005 versus heparin/aspirin). Reocclusion was delayed (406 +/- 329 min), but still occurred in three of six rTAP-treated dogs (p = 0.003 versus heparin/aspirin). Patency after 24 h was 100% in ZK-807834-treated and rTAP-treated dogs compared with 67% in control and 83% in heparin/aspirin-treated dogs. PT was increased 3.7-fold, activated partial thromboplastin time 4.9-fold, and bleeding time 2.5-fold by high dose ZK-807834 compared with 1.2-fold, 11.5-fold, and 2.3-fold, respectively, for heparin/aspirin. Inhibition of FXa with ZK-807834 decreases reocclusion and improves patency of recanalized arteries without increasing bleeding compared with heparin/aspirin.
Abendschein
D R
DR
Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri 63110, USA. dabendsc@imgate.wustl.edu
Baum
P K
PK
Verhallen
P
P
Eisenberg
P R
PR
Sullivan
M E
ME
Light
D R
DR
D000578:Amidines / Q000627:therapeutic use*; D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D001157:Arterial Occlusive Diseases / Q000517:prevention & control* / Q000628:therapy*; D001241:Aspirin / Q000627:therapeutic use; D001760:Bleeding Time; D001780:Blood Coagulation Tests; D003327:Coronary Disease / Q000517:prevention & control* / Q000628:therapy*; D003328:Coronary Thrombosis / Q000517:prevention & control; D004285:Dogs; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006493:Heparin / Q000627:therapeutic use*; D006801:Humans; D017078:Laser-Doppler Flowmetry; D008297:Male; D015425:Myocardial Reperfusion; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D055502:Secondary Prevention; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
D000578:Amidines; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011725:Pyridines; D011994:Recombinant Proteins; C114592:Fidexaban; D006493:Heparin; D010959:Tissue Plasminogen Activator; D001241:Aspirin