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(Circulation. 1995;91:785-793.)
© 1995 American Heart Association, Inc.

Articles

Enhanced Intracoronary Thrombolysis With Urokinase Using a Novel, Local Drug Delivery System

In Vitro, In Vivo, and Clinical Studies

Joseph F. Mitchel, DO; Daniel B. Fram, MD; Donald F. Palme, II, PhD; Rosemary Foster, BSc; Jeffrey A. Hirst, MD; Michael A. Azrin, MD; Laurine M. Bow, PhD; Adel M. Eldin, MD; David D. Waters, MD; Raymond G. McKay, MD

From the Departments of Internal Medicine and Cardiology, Hartford Hospital, University of Connecticut, Hartford.

Correspondence to Raymond G. McKay, MD, Director, Cardiac Laboratory, Hartford Hospital, 80 Seymour St, Hartford, CT 06115.

	Abstract

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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-hole catheter (P<.001). Urokinase deposited by the Dispatch catheter persisted intramurally for at least 5 hours. Patient studies demonstrated reduction of thrombus-containing stenoses and complete disappearance of intracoronary thrombus in all cases in which 150 000 U urokinase was locally infused over 30 minutes. There was no evidence of abrupt closure, distal embolization, or no reflow in any patient.

Conclusions Local urokinase delivery with the Dispatch catheter can result in rapid and complete intracoronary thrombolysis using substantially less drug than standard thrombolytic techniques. Intramural deposition of drug with this technique creates a local reservoir of urokinase that may provide prolonged thrombolytic activity at the infusion site.

Key Words: thrombus • urokinase • drug administration

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
The presence of intracoronary thrombus significantly increases the risk of percutaneous revascularization because of an elevated incidence of abrupt thrombotic closure, distal embolization, and no reflow.^{1 2 3 4 5} Current pharmacological regimens for treating thrombus generally involve the systemic or intracoronary administration of thrombolytic agents that produce a systemic fibrinolytic state and/or require prolonged drug infusion.^{6 7 8 9 10 11 12 13 14 15}

Previous work by our laboratory has recently documented the utility of locally delivering limited quantities of urokinase directly to the angioplasty site to achieve intracoronary thrombolysis using urokinase-coated, hydrogel balloons.¹⁶ The presumed mechanism of this technique involves the "trapping" of thrombus in an environment of relatively high urokinase concentration, resulting in enhanced local thrombolysis. In addition, local delivery of urokinase with urokinase-coated balloons can result in intramural deposition of the drug, with the creation of a local urokinase reservoir that inhibits ongoing platelet deposition and thrombus formation. Although preliminary studies with drug-coated balloons have been promising, this technique is limited by the small amounts of urokinase that can be absorbed by the hydrogel polymer, by wash-off of drug from the balloon surface in the intact circulation, and by the short times of drug delivery required because of ischemia from complete vessel occlusion.

The purpose of the present study was to assess another technique of local urokinase delivery for treating intracoronary thrombus consisting of a recently approved, catheter-based drug delivery system (the Dispatch catheter, Scimed Life Systems). The Dispatch catheter consists of an over-the-wire, nondilatation device with a helical inflation coil on its distal tip. Inflation of the catheter's coils results in the expansion of an inner urethane sheath that allows for distal coronary flow. Local drug delivery with the catheter is achieved through a separate infusion port that delivers therapeutic agents into protected spaces between the catheter's coils. Previous work by our laboratory has documented the efficacy of this device in the local intracoronary delivery of heparin in a porcine model.¹⁷

To assess the potential utility of the Dispatch catheter in achieving local thrombolysis with infusions of urokinase, this study was designed with three specific goals: first, to test in vitro the ability of the Dispatch catheter to dissolve thrombus with local urokinase delivery compared with "systemic" urokinase administration or local infusion of urokinase by standard drug infusion catheters; second, to assess in vivo the safety of prolonged drug infusion with the Dispatch catheter and the ability of the catheter to deliver urokinase intramurally at an angioplasty site; and third, to test in patients the ability of the Dispatch catheter to safely treat intracoronary thrombus before or after percutaneous revascularization.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Equipment
The Dispatch device is an over-the-wire, nondilatation catheter that consists of a 4.4F shaft with a 20-mm polyolefin copolymer spiral inflation coil wrapped around a nonporous urethane sheath on its distal tip. When the spiral coil is inflated, it forms both an internal lumen that allows for distal coronary perfusion through the inner sheath and a series of isolated spaces between the catheter's coils, the urethane sheath, and the arterial wall. Drug is administered through a separate infusion port and is delivered locally through slits in the shaft of the catheter into the protected spaces between the coils of the device. The arterial wall is thus bathed in drug that is isolated from blood flowing through the inner urethane sheath. The catheter is manufactured with 3.0-, 3.5-, and 4.0-mm coil sizes. The catheter coils are inflated with a standard indeflator and are nominal at 6 atm. The structure of the Dispatch catheter is illustrated in Fig 1.

View larger version (36K): [in this window] [in a new window]   Figure 1. Schematic of the Dispatch catheter. Inflation of the catheter's coils results in expansion of an inner urethane sheath that allows for distal blood flow. Drug is delivered through the infusion port into the protected spaces between the catheter's coils.

Urokinase Preparation and Delivery
For in vitro and patient studies, Abbokinase (Abbott Laboratories) was infused with the Dispatch catheter at a concentration of 10 000 U/mL. For in vivo radiolabeled studies,¹²³I-labeled urokinase was used to quantify intramural drug deposition and washout. A total of 125 000 U recombinant urokinase (Abbott Laboratories) was iodinated with 5 mCi ¹²³I (Amersham) by a modified lactoperoxidase method¹⁸ and then suspended in Abbokinase to achieve a final urokinase concentration of 11 000 U/mL and final specific activity of 1 mCi/350 000 U. A known quantity of the radiolabeled urokinase solution was counted in a gamma counter to confirm the relationship between ¹²³I counts per minute and concentration of urokinase. Counts per minute measured from arterial segments were thus converted to units of urokinase after subtraction of background counts. Aliquots of radiolabeled urokinase and arterial segments were counted at the same time to correct for decay of the ¹²³I.

All urokinase infusions with the Dispatch catheter were performed with a volume-driven IMED pump at an infusion rate of 0.5 mL/min.

In Vitro Thrombolysis Experiments
The ability of the Dispatch catheter to dissolve thrombus with local infusions of urokinase was assessed in vitro with the experimental setup diagrammed in Fig 2. A 2-L reservoir of 20% fresh porcine plasma/saline maintained at 37°C served as a source of plasminogen and was used to perfuse a 4-mm-ID, bifurcated plastic tube system (Tygon, Cole Parmer Instruments). The perfusate was pumped through the plastic tube system with a Masterflex peristaltic pump (model 7523, Cole Parmer Instruments). Interposed between the reservoir and the plastic tube bifurcation was both an injection port used for the "systemic" administration of urokinase and a Y adaptor connector used for the introduction of drug-delivery catheters. The bifurcated tube system was immersed in a temperature-controlled tank at 37°C. One of the bifurcated tubes contained a 50% constriction, and the other bifurcating tube allowed for "bleed off" of excess pressure during insertion of thrombus and catheters. A 2.1F Millar catheter (Millar Instruments, Inc) was placed distal to the 50% constriction site through a second Y adaptor. Both bifurcated tubes subsequently emptied into a waste reservoir. Perfusate was pumped through the system at a flow rate of 50 mL/min and at a mean perfusion pressure of 80 mm Hg as measured by the Millar transducer. The total volume of perfusate in the system was 2 L.

View larger version (39K): [in this window] [in a new window]   Figure 2. Schematic of in vitro thrombolysis experiments. Perfusate consisting of 20% porcine plasma was pumped with a peristaltic pump through a plastic tube system at 50 mL/min and a mean pressure of 80 mm Hg. Thrombus samples were placed at the 50% constriction and treated with different interventions.

Fresh porcine thrombus from whole blood was collected and weighed to the nearest 0.1 mg on a Mettler AE200 analytical scale (Mettler Instruments). Thrombus samples 150.0 mg in size were introduced into the flow path and positioned at the site of the 50% constriction. A thrombus of this size would typically occlude the tubing at the constriction site.

Thrombus samples that were placed at the constriction site were subsequently treated with one of five interventions: no treatment (n=5), infusion of 150 000 U urokinase into the drug injection port over 30 minutes ("systemic therapy") (n=4), local infusion of 150 000 U urokinase at the constriction site over 30 minutes through an end-hole catheter (Ultra-Fuse X, Scimed Life Systems) (n=4), local infusion of saline at the constriction site with the Dispatch catheter for 30 minutes (n=5), and local infusion of 150 000 U urokinase at the constriction site with the Dispatch catheter for 30 minutes (n=5). For the "systemic therapy" intervention, fluid from the waste reservoir was continually transferred to the perfusate reservoir to simulate urokinase recirculation. For the end-hole catheter interventions, the distal catheter tips were positioned immediately proximal to the site of thrombus. For all Dispatch interventions, a 4-mm Dispatch catheter was positioned at the thrombus site, and its coils were inflated to 6 atm. All thrombi were weighed immediately before and 30 minutes after initiation of the intervention.

In Vivo Dispatch Experiments
A total of 23 male Yorkshire swine 3 to 4 months old and weighing 30 to 40 kg were used for an in vivo protocol designed to assess the safety of a prolonged (eg, 30 minutes) intracoronary infusion of urokinase with the Dispatch catheter and to quantify intramural urokinase deposition at an angioplasty site with this technique. All animals were premedicated with Tiletamine/Zolazepam (100 mg IM) and atropine (2 mg IM), anesthetized with pentobarbital, and endotracheally intubated. Anesthesia was maintained with enflurane 1% to 3%, and ventilation was provided by a volume respirator.

By standard surgical technique, a 9F introducer sheath (Cordis Corp) was inserted into the right external carotid artery by direct arterial exposure. To prevent thrombosis of the vascular sheath, all animals received a single bolus of 200 U/kg heparin at the onset of surgery and 100 U/kg each hour thereafter while anesthetized. Coronary angiography of the left or right coronary artery was then performed using 9F "hockey stick" or left amplatz guiding catheters (Cordis Corp) with hand injections of contrast.

In all arteries evaluated, conventional balloon angioplasty was initially performed with a standard angioplasty catheter (Boston Scientific) inserted over a 0.014-in angioplasty guide wire (Advanced Cardiovascular Systems). One 60-second inflation was performed with a balloon/artery ratio of approximately 1:1 and an inflation pressure of 8 atm. Balloon sizes ranged from 3 to 4 mm.

In 16 dilated arteries in 16 pigs, a Dispatch catheter was then inserted over a 0.014-in angioplasty guide wire, and its coils were inflated to 6 atm at the angioplasty site with a balloon/artery ratio of 1:1. For any given artery, the size of the Dispatch catheter was the same as the conventional angioplasty balloon that was originally used to dilate the vessel. Subsequently, 150 000 U ¹²³I-labeled urokinase was infused with the Dispatch catheter at the angioplasty site over 30 minutes. Systemic blood pressure and surface ECG leads II and V₅ were monitored continuously throughout the time of Dispatch use and drug infusion. TIMI coronary flow grade at baseline and during drug infusion was assessed by serial coronary injections of contrast every 5 minutes. After local urokinase infusion, animals were killed and arteries were harvested either immediately (n=4), at 30 minutes (n=3), at 60 minutes (n=3), at 2 hours (n=3), or at 5 hours (n=3). The distribution of treated arteries included the left anterior descending in 6 cases, the circumflex in 5 cases, and the right coronary artery in 5 cases. In each animal, an additional undilated artery that was not treated with the Dispatch catheter was also harvested to serve as a control. Arteries were then counted in a gamma counter to quantify intramural deposition of radiolabeled drug at the angioplasty site.

In an additional 9 dilated arteries in 7 pigs, intramural deposition of urokinase was also determined after an intravenous systemic bolus of 1 000 000 U ¹²³I-labeled urokinase (n=3), after infusion of 500 000 U ¹²³I-labeled urokinase through the guiding catheter (n=3), or after the local infusion of 150 000 U urokinase at the angioplasty site through an end-hole catheter (Ultra-Fuse X, Scimed Life Systems) (n=3). Arteries were harvested 15 minutes after systemic bolus or immediately after urokinase infusion with guiding catheters or end-hole catheters for gamma counting. An undilated artery was also obtained from each animal to serve as a control.

All animal studies conformed to the principles of the American Physiological Society. Investigational use of the Dispatch catheter in animals was approved by the Hartford Hospital Institutional Review Board.

Clinical Studies
Localized infusion of 150 000 U urokinase over 30 minutes with the Dispatch catheter was attempted in 19 consecutive patients with angiographic evidence of intracoronary thrombus. Four of these patients were described in a previous manuscript.¹⁹ All patients gave informed consent for localized drug delivery. Clinical studies were performed after approval of the Dispatch device by the US Food and Drug Administration as a drug infusion catheter; specific approval of Dispatch use in patients, therefore, was not obtained by the Hartford Hospital Institutional Review Board.

The extent of intracoronary thrombus in each patient was graded on a thrombus score of 0 to 3 as described in Table 1. Possible intracoronary thrombus (grade 1) was identified at stenosis sites in which there was reduced contrast density, intraluminal haziness, irregular lesion contour, or a smooth convex "meniscus" at the site of a total occlusion. Definite intracoronary thrombus (grade 2 or 3) was identified as a clearly localized, discrete intraluminal filling defect that was surrounded by contrast medium on at least three sides and was seen in multiple views.

View this table: [in this window] [in a new window]   Table 1. Determination of Thrombus Score

Intracoronary thrombus was treated before balloon angioplasty or directional atherectomy in 10 patients and after angioplasty or atherectomy in 9 patients. In all cases, the Dispatch catheter was positioned at the thrombus site over a 0.014-in angioplasty guide wire. The catheter's coils were then inflated to 6 atm, and urokinase was infused at 10 000 U/mL and 0.5 mL/min. Continuous monitoring of systemic blood pressure and three surface-lead ECG leads was made during Dispatch use. Before urokinase infusion and at subsequent 5-minute intervals, coronary angiography and a seven-lead ECG (leads I, II, III, aVR, aVL, aVF, and V₅) were obtained.

Data Analysis
Mean and SD were determined for all variables. Intergroup comparisons of thrombus dissolution in the in vitro studies and intramural urokinase deposition in the in vivo studies were performed by ANOVA, followed by unpaired two-tailed Student's t tests with the Bonferroni correction.

For patient studies, all angiograms were reviewed by two observers who independently evaluated the angiographic thrombus score and TIMI coronary flow grade. Differences were resolved by consensus. A paired two-tailed Student's t test was performed to compare thrombus score and TIMI flow before and after use of the Dispatch catheter.

Quantitative coronary analysis was performed on all coronary lesions treated with the Dispatch catheter. End-diastolic cine frames, selected whenever possible from orthogonal projections, were analyzed before and after Dispatch use and conventional angioplasty/directional atherectomy. The selected cine frames were digitized with a cine-video converter, and a computer-assisted edge-detection algorithm was applied to the arterial and catheter contours (Cardiovascular Measurement System). With the guiding catheter used as the calibration standard, reference and minimal lumen diameters were determined. A paired two-tailed Student's t test was performed to compare percent stenosis and minimal lumen diameter before and after use of the Dispatch catheter.

A value of P<.05 was considered significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
In Vitro Thrombolysis Studies
Table 2 lists the results of in vitro thrombolytic experiments. Local delivery of urokinase with the Dispatch catheter resulted in a 66% reduction of thrombus weight compared with no treatment (-25%), "systemic" urokinase infusion (25%), local urokinase infusion with an end-hole catheter (32%), or local saline infusion with the Dispatch catheter (32%) (P.005 for Dispatch urokinase infusion versus all other techniques). Four of the five thrombus specimens in the "no treatment" group actually increased in weight.

View this table: [in this window] [in a new window]   Table 2. In Vitro Thrombolysis

In Vivo Porcine Studies
A 30-minute infusion of urokinase via the Dispatch catheter was tolerated in all 16 dilated porcine arteries without significant arrhythmias or change in systemic blood pressure. In 5 arteries, significant ST-segment depression on surface ECG leads was noted during Dispatch use and was thought to be secondary to occlusion of arterial side branches by the catheter's coils. TIMI 3 flow was noted in 14 of the 16 arteries during drug infusion. In the remaining 2 arteries, transient vasospasm with TIMI 1 flow was noted distal to the Dispatch catheter and was successfully reversed with intracoronary administration of 100 to 300 µg of nitroglycerin.

Table 3 lists intramural deposition and washout of urokinase at the angioplasty site in the 16 porcine arteries that were treated with the Dispatch catheter. Immediately after delivery of 150 000 U, 179±79 U (0.12±0.05% of administered drug) was detected intramurally. The percentage of intramural drug decreased significantly by 30 minutes, remained relatively constant until 2 hours, and then decreased further by 5 hours. At the 5-hour interval, 0.004±0.0015% of administered drug was still detected at the angioplasty site. Undilated control arteries all contained <1 U radiolabeled urokinase.

View this table: [in this window] [in a new window]   Table 3. Urokinase Deposition and Washout With the Dispatch Catheter

Table 4 compares intramural deposition of radiolabeled urokinase at angioplasty sites with the four different techniques of drug infusion. More intramural urokinase was detected at the angioplasty site immediately after infusion of 150 000 U urokinase with the Dispatch catheter (178±79 U, 0.12±0.05%) than with a 1 000 000–U systemic bolus (6.8±0.5 U, 0.0007±0.00004%), infusion of 500 000 U through a guiding catheter (16.3±6.1 U, 0.003±0.001%), or local infusion of 150 000 U with an end-hole infusion catheter (11.0±8.2 U, 0.007±0.005%) (P<.001 for Dispatch compared with all other interventions).

View this table: [in this window] [in a new window]   Table 4. Comparison of Intramural Deposition With Different Urokinase Administration Techniques

Clinical Studies
Local infusion of urokinase with the Dispatch catheter was performed before or after percutaneous revascularization in 19 patients with evidence of intracoronary thrombus. Patient demographics are described in Table 5. The study group consisted of 10 men and 9 women with a mean age of 60 years. Clinical diagnoses included unstable angina in 9 patients, acute myocardial infarction in 8 patients, and postinfarction angina in the remaining 2 patients. Indications for Dispatch use included pretreatment of intracoronary thrombus before conventional angioplasty (n=8) or directional atherectomy (n=2) (patients 1 through 10; Tables 5 and 6), or treatment of residual thrombus after angioplasty (n=8) or atherectomy (n=1) (patients 11 through 19, Tables 5 and 7). The site of Dispatch use included the right coronary artery (n=8), the left anterior descending artery (n=6), the circumflex artery (n=1), or a saphenous vein graft (n=4). Total occlusions were present at the site of Dispatch use in 5 patients. Collateral vessels to the Dispatch-treated artery were seen on angiography in 6 patients. All patients were pretreated with aspirin and intravenous heparin with an activated coagulation time >300 seconds before Dispatch use. No patient had received systemic thrombolytic therapy.

View this table: [in this window] [in a new window]   Table 5. Clinical and Angiographic Features of Patients Treated With the Dispatch Catheter

View this table: [in this window] [in a new window]   Table 6. Quantitative Coronary Angiographic Findings in Patients Treated With the Dispatch Catheter Before Conventional Angioplasty or Atherectomy

View this table: [in this window] [in a new window]   Table 7. Quantitative Coronary Angiographic Findings in Patients Treated With the Dispatch Catheter After Conventional Angioplasty or Atherectomy

In one of the 19 patients (patient 2, Tables 5 and 6), urokinase infusion with the Dispatch catheter before balloon angioplasty at a proximal left anterior descending site was tolerated for only 5 minutes because chest pain, significant ST-segment depression, and frequent premature ventricular contractions developed. Angiography demonstrated TIMI grade 3 flow before Dispatch therapy and TIMI grade 1 flow during Dispatch use. The presence of a severe proximal left anterior descending lesion was thought to have prevented complete expansion of the inner Dispatch urethane sheath to allow for adequate distal perfusion. The Dispatch catheter was subsequently removed with return of normal TIMI flow and cessation of chest pain. Angiography demonstrated no change in the left anterior descending thrombus-containing stenosis. The patient was subsequently treated with conventional balloon angioplasty without complications.

In the remaining 18 patients, Dispatch catheter use was well tolerated with local infusion of 150 000 U urokinase over 30 minutes without change in systemic blood pressure or cardiac rhythm. One of the 18 patients experienced chest pain and mild ST-segment depression during drug infusion, thought to be secondary to occlusion of a right coronary artery acute marginal branch by the catheter's coils. Mild vasospasm distal to the Dispatch catheter was noted in 2 additional patients and was successfully treated with intracoronary nitroglycerin. TIMI grade 3 flow was noted in 15 of the 18 patients during Dispatch use, with TIMI grade 2 flow in the remaining 3 patients.

In all patients in which the Dispatch catheter was deployed for 30 minutes, there was complete angiographic resolution of intracoronary thrombus. For the entire group of 19 patients, thrombus score decreased from 2.1±0.7 to 0.1±0.5 (P=.0001), and TIMI flow increased from grade 2.1±1.4 to 3.0±0.0 (P<.007).

Table 6 summarizes quantitative coronary angiographic measurements for the 10 patients in whom the Dispatch catheter was used before conventional angioplasty or atherectomy. In these patients, the baseline percent stenosis of the treated lesion decreased from 84±11% to 48±16% after Dispatch therapy and decreased further to 21±10% after angioplasty/atherectomy. Similarly, minimal lumen diameters at the stenosis site increased from 0.50±0.36 to 1.63±0.58 mm after Dispatch and to 2.39± 0.45 mm after angioplasty/atherectomy.

Table 7 summarizes quantitative coronary angiographic measurements in the remaining 9 patients in whom the Dispatch catheter was used to treat residual thrombus after conventional angioplasty or atherectomy. The percent stenosis decreased from 94±11% at baseline, to 65±27% after angioplasty/atherectomy, and finally to 31±8% after Dispatch therapy. Minimal lumen diameters increased from 0.17±0.31 mm at baseline, to 0.98±0.76 mm after angioplasty/atherectomy, and to 1.89±0.30 mm after Dispatch.

Abrupt closure, distal embolization, and no-reflow phenomena were not identified in any of the 19 patients either during or after Dispatch use. After use of the Dispatch catheter, all patients were treated with intravenous heparin, aspirin, and a combination of nitrates, calcium channel blockers, and ß-blockers. No patient demonstrated clinical evidence of coronary reocclusion or increased elevation of baseline cardiac enzymes. Two patients developed mild hematomas at the femoral arteriotomy insertion site, but no patient required transfusion or vascular repair. No other clinical bleeding episodes were noted in the study group. All patients were subsequently discharged from the hospital.

Fig 3 illustrates a patient with an acute myocardial infarction in whom the Dispatch catheter was used to treat intracoronary thrombus before coronary angioplasty.

View larger version (322K): [in this window] [in a new window]   Figure 3. Clinical example of Dispatch use. Left anterior oblique angiograms of the right coronary artery (RCA) of a 52-year-old man with an acute inferior wall myocardial infarction demonstrating a totally occluded proximal vessel (A), a severe stenosis and intraluminal filling defect representing intracoronary thrombus (arrows) after placement of an angioplasty guide wire across the RCA total occlusion (B), placement of the Dispatch catheter at the site of thrombus (C), and moderate reduction of the stenosis with dissolution of the thrombus after local urokinase delivery (D). TIMI grade 3 flow was noted during use of the Dispatch catheter. After dissolution of intracoronary thrombus with the Dispatch catheter, conventional balloon angioplasty resulted in further reduction of the residual proximal stenosis (E).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This study demonstrates the efficacy of a new catheter-based drug-delivery system for the local infusion of urokinase to treat intracoronary thrombus. In vitro studies with this technique have demonstrated significantly more lysis of preexisting clot compared with "systemic" urokinase therapy, local infusion of urokinase with conventional drug-delivery catheters, or local infusion of saline with the Dispatch catheter. In vivo studies have demonstrated safe use of the Dispatch catheter in a porcine model and significant intramural deposition of urokinase at angioplasty sites that persisted for at least 5 hours. Studies in humans have demonstrated that the catheter is able to reduce thrombus-containing stenoses and lyse thrombotic filling defects in a variety of acute coronary syndromes while still maintaining distal coronary perfusion. Most important, use of the Dispatch catheter in these patients resulted in rapid and successful thrombolysis using significantly less drug than standard thrombolytic techniques.

Potential Mechanisms of Action
The presumed mechanism of enhanced thrombolysis with the Dispatch catheter involves the "trapping" of intraluminal thrombus between the catheter's coils, in a protected local environment of high urokinase concentration that is isolated from the coronary blood flow. Previous in vitro studies with human plasma demonstrated that a urokinase concentration of at least 100 U/mL is required to initiate significant clot lysis.²⁰ In the present study, urokinase infused into the protected spaces between the catheter's coils may have resulted in a local drug concentration approximating 10 000 U/mL. This high local urokinase concentration presumably acts directly on circulating plasminogen or on plasminogen trapped within the thrombus to create plasmin.

A second potential mechanism of local urokinase therapy with the Dispatch catheter involves intramural deposition of the drug at the angioplasty site. Compared with standard thrombolytic therapy, use of the Dispatch catheter resulted in 10 to 26 times more intramural urokinase than systemic urokinase administration, guiding catheter infusion, or local infusion with an end-hole catheter. Moreover, the efficiency of intramural delivery (eg, percentage of administered drug deposited intramurally) is 17 to 170 times greater with the Dispatch catheter than with these other techniques. Theoretically, intramural deposition of urokinase may create a small reservoir of drug at the angioplasty site that slowly elutes from the arterial wall into the bloodstream, resulting in a prolonged, local thrombolytic effect. Persistent effects of intramural urokinase on the inhibition of platelet deposition at an angioplasty site have been documented by our laboratory when urokinase-coated hydrogel balloons were used.¹⁶

A local reservoir of urokinase created by the Dispatch catheter would bypass the normal hepatic extraction and inactivation of urokinase, which usually occurs within 15 minutes of a systemic urokinase bolus.⁷ Thus, Dispatch urokinase therapy may not only "trap" thrombus in an environment of high urokinase concentration during catheter use but also intramurally "trap" urokinase at the angioplasty site for a prolonged time period after catheter removal. Although the present study measured persistence of intramural drug for only 5 hours, previous animal work by our laboratory has demonstrated that intramural heparin delivered with the Dispatch catheter can be detected for at least 96 hours.¹⁷ Additional studies are needed to further characterize the functional significance and time course of washout of intramural urokinase deposited with the Dispatch system.

A final mechanism of the localized thrombolysis with the Dispatch catheter may involve prolonged compression and subsequent mechanical disruption of intraluminal clot by the catheter's inflated coils. In part, this mechanism may serve to increase the thrombus surface area available for urokinase action. As indicated in the in vitro thrombolysis studies described in Table 2, however, simple prolonged Dispatch use without the addition of urokinase also resulted in significant decrease in thrombus weight. This technique of mechanical disruption is presumably the same mechanism by which intraluminal clot is treated by conventional balloon angioplasty.

Clinical Implications
Intracoronary thrombus is an extremely common and difficult problem to treat in the cardiac catheterization laboratory. Depending on whether it is identified by angiography or angioscopy, the incidence of intracoronary thrombus ranges from 6% to 15% in patients referred for percutaneous revascularization to 40% to 90% in patients with unstable coronary syndromes.^{21 22 23 24 25} During percutaneous revascularization, thrombus formation may be further accelerated by exposure of arterial wall components to circulating platelets and by release of platelet factor IV and fibrin-bound thrombin from intraluminal clot. As a result, conventional balloon angioplasty in the presence of intracoronary thrombus may result in abrupt closure rates as high as 73%, in distal embolization rates as high as 31%, and in an incidence of no-reflow phenomenon as high as 7%.²⁶

The efficacy of administering urokinase and other thrombolytic agents either systemically or locally to treat intracoronary thrombus has been documented in multiple nonrandomized trials.^{6 7 8 9 10 11 12 13 14 15} More recently, improved thrombolysis has been demonstrated with the use of subselective catheters and prolonged urokinase infusions directly to the site of thrombus.^{12 15} Use of these techniques, however, generally involves the administration of doses of urokinase that result in a systemic fibrinolytic state and/or require prolonged arterial drug infusions (eg, 18 to 48 hours).

Compared with conventional balloon angioplasty and standard adjunctive pharmacological regimens, local delivery of urokinase directly to the site of intracoronary thrombus with the Dispatch catheter may have specific advantages. Apart from theoretically decreasing the incidence of abrupt closure, distal embolization, and no reflow, use of the Dispatch catheter may avoid the need for prolonged administration of antithrombin and thrombolytic agents that lengthen the patient's hospitalization and catheterization procedure. A second advantage of this approach is that a much lower dose of drug can be administered to the patient, thereby preventing systemic thrombolysis and subsequent bleeding complications. This may be particularly useful in patients who have contraindications to systemic thrombolysis.

Technical Aspects of Dispatch Catheter Use
Compared with other local drug delivery systems, the major advantage offered by the Dispatch catheter is that it allows for prolonged administration of therapeutic agents while still maintaining distal coronary perfusion. Theoretically, any given amount of drug can be administered to an angioplasty site by simply altering the concentration of the infused agent and the drug infusion time.

On the basis of the present study and previous animal work from our laboratory,¹⁷ it is also apparent that the Dispatch catheter has several limitations. First, the device may result in significant ischemia from side-branch occlusion by the catheter's coils. Second, the catheter has limited ability to dilate a coronary stenosis. As a result, use of the catheter within an undilated coronary stenosis may result in incomplete expansion of the inner urethane sheath and inadequate distal perfusion. Finally, use of the catheter in an undersized artery may similarly prevent complete inflation of the catheter's coils and expansion of the inner urethane sheath with inadequate distal perfusion. Any of these limitations may prevent prolonged use of the Dispatch catheter at the angioplasty site and limit the time of intracoronary drug infusions.

Limitations of the Study
Although locally delivered urokinase resulted in reduction of thrombus-containing stenoses and dissolution of intracoronary clot in this study, it is impossible to rule out that these angiographic findings occurred partly because of prolonged mechanical compression of atheromata and thrombus by the Dispatch catheter's coils. Second, although successful thrombolysis was noted with 150 000 U urokinase, additional studies need to be done to determine the optimal dose of infused drug in relation to any given clot burden. Finally, compared with angioscopy, the angiographic identification of intracoronary thrombus has its limitations.^{23 24} A randomized, controlled trial of local urokinase delivery, perhaps involving several different drug doses and coronary angioscopy to identify thrombus, would be necessary to ascertain the maximum potential benefit of this technique. Additional studies with other thrombolytic drugs, including agents that are more "clot specific" with increased fibrin binding, may also be warranted.

Conclusions
Local urokinase delivery with the Dispatch catheter is possible and appears to be efficacious in treating intracoronary thrombus and thrombus-containing stenoses with drug doses that are substantially less than conventional thrombolytic techniques. Intramural deposition of urokinase at the site of the drug infusion may provide for prolonged local thrombolytic activity. A randomized, controlled trial of this therapy may be useful in evaluating the efficacy of this technique.

	Footnotes

 
D.F.P. and R.F. are currently employed by Scimed Life Systems.

Received June 22, 1994; accepted September 23, 1994.

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