Maintenance of canine coronary artery patency following thrombolysis with front loaded plus low dose maintenance conjunctive therapy. A comparison of factor Xa versus thrombin inhibition.
OBJECTIVE
The aim was to examine the abilities of the direct thrombin inhibitor, recombinant hirudin (rHIR), and the coagulation factor Xa inhibitor, recombinant tick anticoagulant peptide (rTAP), given in combination with rt-PA as high dose front loading plus low dose maintenance infusions, to enhance reperfusion and maintain vessel patency in a canine model of left circumflex coronary artery stenosis and electrolytic lesion.


METHODS
Occlusive coronary artery thrombosis was induced in anaesthetised dogs by electrical injury (150 microA) of the intimal surface of the vessel. Thirty minutes after occlusive thrombosis, high dose front loading infusions (45 min) of rTAP (200 micrograms.kg-1 x min-1) and rHIR (300 micrograms.kg-1 x min-1) were initiated concomitant with the start of a 90 min infusion of recombinant tissue-type plasminogen activator (rt-PA). Following the termination of front loading infusions, maintenance infusions of rTAP (10 or 20 micrograms.kg-1 x min-1) or rHIR (20 micrograms.kg-1 x min-1) were initiated and continued for the duration of the protocol (180 min after rt-PA termination).


RESULTS
Reperfusion was incomplete in the rHIR group (7/9; 78%), whereas all rTAP-treated preparations reperfused (8/8 per group, aggregate 16/16; 100%). Following thrombolysis, the rHIR group had a high incidence of reocclusion, ranging from intermittent to long periods of occlusion, with only 2/7 (29%) of the preparations which initially recanalised remaining patent during the 180 min period following rt-PA termination. In contrast, 5/8 preparations in each of the two rTAP groups [aggregate 10/16; 63%] remained patent during the same period. The greater efficacy of rTAP v rHIR in maintaining vessel patency was also reflected in integrated coronary artery blood flows [91.0(SEM 5.8)% and 84.9(6.1)% of preocclusion flow in rTAP groups v 57.5(12.2)% of preocclusion flow in rHIR group], times to reocclusion [123.3(22.8) and 128.0(6.7) min in rTAP groups v 36.6(23.2) min in rHIR group; p < 0.05], and residual thrombus masses [1.8(0.3) and 2.0(0.3) mg in rTAP groups v 10.4(3.8) mg in rHIR group; p < 0.05].


CONCLUSIONS
With the present front loading plus low dose maintenance infusions designed to limit the duration of "high dose" conjunctive therapy, rTAP was more effective than rHIR at equimolar plasma concentrations in maintaining post-thrombolysis vessel patency, preserving coronary artery blood flow, and reducing residual thrombus mass. These findings further support the therapeutic potential of inhibiting factor Xa in the setting of coronary artery thrombolysis.
Lynch
J J
JJ
Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486.
Sitko
G R
GR
Mellott
M J
MJ
Nutt
E M
EM
Lehman
E D
ED
Friedman
P A
PA
Dunwiddie
C T
CT
Vlasuk
G P
GP
D000818:Animals; D060829:Arthropod Proteins; D003327:Coronary Disease / Q000188:drug therapy*; D004285:Dogs; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D065427:Factor Xa Inhibitors; D005260:Female; D024764:Hirudin Therapy; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D010455:Peptides / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012008:Recurrence; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D014654:Vascular Patency / Q000187:drug effects*
D060829:Arthropod Proteins; D065427:Factor Xa Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D011994:Recombinant Proteins; C063967:tick anticoagulant peptide; D010959:Tissue Plasminogen Activator