Comparison of a low-molecular-weight heparin (nadroparin calcium) and unfractionated heparin as adjunct to coronary thrombolysis with alteplase and aspirin in dogs.
BACKGROUND
Low-molecular-weight heparins may have a higher benefit to risk ratio than unfractionated heparin in preventing perioperative thrombosis. The antithrombotic effects of low-molecular-weight heparins, given as adjunctive therapy to alteplase and aspirin, have not previously been compared with those of unfractionated heparin in experimental models of coronary artery thrombosis.


METHODS
Occlusive coronary thrombosis was induced in 5 groups of 10 dogs by placing a copper coil into the left anterior descending coronary artery. After 1 h of occlusion, intravenous alteplase (0.1 mg/kg bolus followed by 0.01 mg/kg/min for 30 min), and aspirin (bolus of 5 mg/kg) were administered in combination with one of the following study treatments given intravenously for 2 h: placebo (group 1); unfractionated heparin (200 IU/kg bolus followed by 100 IU/kg/h, group II); the low-molecular weight heparin, nadroparin calcium, in three different doses (100 IU/kg bolus followed by 50 IU/kg/h, group III; 200 IU/kg bolus followed by 100 IU/kg/h, group IV; and 300 IU/kg followed by 150 IU/kg/h, group V). Coronary patency was assessed with angiography at 10 min intervals and hemostasis parameters were measured at baseline, after 1 h of occlusion, and 30 and 120 min after commencing drug administration.


RESULTS
Optimal reperfusion [Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 without reocclusion] was more frequently observed in groups II (6/10), IV (8/10) and V (9/10) than in groups I (1/10) and III (3/10) (P < 0.05). Groups II and IV had similar patency rates (P = NS) and were therefore assumed to represent equivalent antithrombotic doses. Both nadroparin calcium and unfractionated heparin effectively prevented new thrombin generation as shown by repeated measurements of thrombin-antithrombin III complex levels in plasma. At equivalent antithrombotic doses, nadroparin calcium (group IV) was associated with significantly lower steady state values than standard heparin (group II) for activated partial thromboplastin time (41.3 +/- 48.9 versus 134.7 +/- 61.6 s), anti-Xa levels (2.4 +/- 0.5 vs 3.4 +/- 0.9 U/ml) and anti-IIa levels (0.8 +/- 0.1 versus 2.1 +/- 0.7 U/ml).


CONCLUSIONS
Both nadroparin calcium and unfractionated heparin significantly enhance alteplase-induced thrombolysis in aspirin-treated dogs. At equivalent antithrombotic doses, nadroparin calcium was associated with less prolongation of the activated partial thromboplastin time and lower steady-state anti-Xa and anti-IIa activities.
Jun
L
L
Laboratory of Experimental Cardiology, University of Leuven, Belgium.
Arnout
J
J
Vanhove
P
P
Dol
F
F
Lormeau
J C
JC
Herbert
J M
JM
Collen
D
D
Van de Werf
F
F
D000818:Animals; D001241:Aspirin / Q000008:administration & dosage*; D003328:Coronary Thrombosis / Q000188:drug therapy*; D004285:Dogs; D006493:Heparin / Q000008:administration & dosage*; D015425:Myocardial Reperfusion; D017762:Nadroparin / Q000008:administration & dosage*; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*
D017762:Nadroparin; D006493:Heparin; D010959:Tissue Plasminogen Activator; D001241:Aspirin