Catheter-based local thrombolysis with urokinase: comparative efficacy of intraluminal clot lysis with conventional urokinase infusion techniques in an in vivo porcine thrombus model.
Local delivery of urokinase directly to the site of intraluminal clot using catheter-based technology has recently been introduced as a new technique to treat intracoronary thrombus and thrombus-containing stenoses. The purpose of this study was to compare the efficacy of urokinase therapy administered by local drug-delivery catheters with conventional urokinase-infusion techniques in dissolving intraluminal clot and intramurally depositing drug at the site of arterial injury in an in vivo porcine model. Five techniques of urokinase administration were studied in 65 pigs, including intravenous systemic bolus (1,000,000 units), guiding catheter infusion (500,000 units), local intraluminal infusion with a Roubin catheter (150,000 units), local infusion by the Dispatch catheter (150,000 units), and local delivery by the hydrogel-coated balloon (700 units). All five techniques were initially compared with respect to the quantity of intraluminal lysis of 123I-fibrinogen-labeled thrombus in an in vivo thrombus model. Conventional balloon angioplasty was also assessed in this model as a nonpharmacologic, mechanical control. In addition, all five techniques were compared with respect to the quantity and efficiency of intramural urokinase deposition at coronary angioplasty sites. In the in vivo thrombolysis experiments, the quantity of artificial clot lysis measured 6.8% for systemic therapy, 20.8% for guiding catheter infusion, 25.2% for Roubin catheter infusion, 62.8% for Dispatch catheter infusion, 98.8% for hydrogel balloon delivery, and 53.6% for conventional balloon angioplasty. Both the Dispatch catheter and the hydrogel balloon resulted in more clot lysis than the systemic, guiding catheter, or Roubin catheter approaches (P < 0.05). In comparison with conventional balloon angioplasty, only the hydrogel balloon resulted in higher levels of thrombus dissolution (P < 0.05). In the intramural deposition studies, the efficiency of urokinase delivery was 0.0004% for systemic therapy, 0.004% for guiding catheter infusion, 0.004% for Roubin catheter infusion, 0.08% for Dispatch catheter infusion, and 1.8% for hydrogel balloon delivery. The Dispatch catheter resulted in higher intramural drug levels than did all other techniques (P < 0.05), whereas the efficiency of urokinase deposition was higher with the hydrogel balloon than with all other approaches (P < 0.05). In the porcine model, it is subsequently concluded that local delivery of urokinase by catheter-based techniques can result in more complete lysis of intraluminal thrombus by using similar or lower doses of drug than by using conventional urokinase infusion techniques. Mechanical deformation of thrombus, possibly to increase the surface area available for thrombolysis and to physically disrupt clot, may be an important component of the mechanism of site-specific thrombolysis, particularly with the hydrogel balloon. Local delivery techniques also deposit significant quantities of urokinase at balloon angioplasty sites, creating an intramural reservoir of drug that may result in prolonged local thrombolysis.
Mitchel
J F
JF
Department of Internal Medicine, Hartford Hospital, University of Connecticut 06115, USA.
Shwedick
M
M
Alberghini
T A
TA
Knibbs
D
D
McKay
R G
RG
D015906:Angioplasty, Balloon, Coronary / Q000295:instrumentation*; D000818:Animals; D003328:Coronary Thrombosis / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000295:instrumentation*; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008854:Microscopy, Electron; D013552:Swine; D015912:Thrombolytic Therapy / Q000295:instrumentation*; D016896:Treatment Outcome; D014568:Urokinase-Type Plasminogen Activator / Q000008:administration & dosage* / Q000493:pharmacokinetics
D005343:Fibrinolytic Agents; D014568:Urokinase-Type Plasminogen Activator