Comparison of hirudin and heparin as adjuncts to streptokinase thrombolysis in a canine model of coronary thrombosis.
Recombinant desulfatohirudin (HI), a potent and specific thrombin inhibitor, was compared with heparin (HE) as an adjunct to streptokinase thrombolysis. In pentobarbital-anesthetized dogs, an occlusive thrombus (whole blood+thrombin) was introduced into the left anterior descending coronary artery (LAD) with superimposed endothelial damage and distal high-grade stenosis. Intravenous infusion of saline (vehicle), HI (0.3 mg/kg followed by 0.3 mg/kg per hour, 1 mg/kg followed by 1 mg/kg per hour, or 2 mg/kg followed by 2 mg/kg per hour), or HE (60 units/kg followed by 40 units/kg per hour or 100 units/kg followed by 60 units/kg per hour) was initiated 15 minutes before streptokinase (750,000 units for 60 minutes) administration. Vessel patency was monitored for 180 minutes after streptokinase administration with a volume flow probe on the proximal LAD. In dogs treated with no adjunctive agent (saline control), none of the vessels were recanalized with streptokinase. Both HI and HE promoted reperfusion, inhibited reocclusion, and reduced the residual thrombus mass in a dose-dependent fashion. However, at comparable levels of therapeutic anticoagulation (activated partial thromboplastin time [APTT] = 1.5-2.0 times baseline) HI exhibited a higher incidence of reperfusion (eight of eight dogs [100%] versus one of eight dogs [12%]), a shorter time to reperfusion (33 +/- 6 versus 59 minutes), a longer duration of initial reperfusion (106 +/- 21 versus 10 minutes), and a smaller residual thrombus mass than did HE. Likewise, the slope of the relation between the APTT prolongation and the total reperfusion time ("anticoagulation/antithrombosis profile") was almost five times higher for the combined HI data than for the HE data. Our results indicate that HI is more effective than HE in enhancing and sustaining coronary recanalization with streptokinase at a HI dose that modestly prolongs coagulation time and does not alter bleeding times.
Rigel
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DF
Research Department, CIBA-GEIGY Corp., Summit, N.J. 07901.
Olson
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RW
Lappe
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RW
D000818:Animals; D003328:Coronary Thrombosis / Q000188:drug therapy*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006493:Heparin / Q000627:therapeutic use*; D024764:Hirudin Therapy; D006629:Hirudins / Q000031:analogs & derivatives*; D008297:Male; D015425:Myocardial Reperfusion; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011994:Recombinant Proteins / Q000627:therapeutic use; D012008:Recurrence; D013300:Streptokinase / Q000627:therapeutic use*; D013997:Time Factors
D005343:Fibrinolytic Agents; D006629:Hirudins; D011994:Recombinant Proteins; D006493:Heparin; D013300:Streptokinase; C060225:desirudin