Enhanced intracoronary thrombolysis with urokinase using a novel, local drug delivery system: In vitro, in vivo, and clinical studies

Abstract

Background: Current pharmacological regimens for treating intracoronary thrombus in the cardiac catheterization laboratory generally involve the administration of thrombolytic agents that result in a systemic fibrinolytic state and/or require prolonged arterial drug infusion. The purpose of the present study was to assess a new technique for treating intracoronary thrombus consisting of the local infusion of limited quantities of urokinase with a novel drug delivery device. Methods and Results: The Dispatch coronary infusion catheter is a new local drug delivery system that allows for the prolonged infusion of therapeutic agents at an angioplasty site while distal coronary flow is maintained. Three experimental protocols were performed to determine the in vitro, in vivo, and clinical efficacy of this device. First, in vitro thrombolysis of fresh, porcine thrombus trapped in a 4-mm plastic tube with a 50% constriction and perfused with 20% porcine plasma was measured. Twenty-three thrombi were weighed before and after no treatment (n=5), 'systemic' urokinase administration (n=4), local infusion of 150 000 U urokinase with a standard end-hole catheter (n=4), local infusion of saline with the Dispatch catheter (n=5), and local infusion of 150 000 U urokinase with the Dispatch catheter (n=5). Second, 25 porcine coronary arteries in 23 pigs were dilated in vivo with conventional balloon angioplasty and then treated with 123I-labeled urokinase that was administered either by the Dispatch catheter (150 000 U; n=16), intravenous systemic bolus (1 000 000 U; n=3), guiding catheter infusion (500 000 U; n=3), or local end-hole catheter infusion (150 000 U; n=3). All vessels were subsequently harvested to quantify intramural deposition and subsequent washout of urokinase at the angioplasty site. Finally, 19 patients with angiographic evidence of intracoronary thrombus were treated with local urokinase infusion with the Dispatch catheter either before or after balloon angioplasty or directional atherectomy. In vitro studies demonstrated that infusion of urokinase with the Dispatch catheter decreased thrombus weight by 66% compared with no treatment (-25%). 'systemic' urokinase administration (25%), end-hole catheter urokinase infusion (32%), or infusion of saline by the Dispatch catheter (32%) (P≤.005). In vivo studies demonstrated immediate deposition of 0.12% of the urokinase delivered by the Dispatch catheter to the angioplasty site, compared with 0.0007% with systemic bolus, 0.003% with guiding catheter infusion, and 0.007% with local infusion with an end-hold catheter (P