Dose-ranging trial with a recombinant urokinase (urokinase alfa) for occluded central venous catheters in oncology patients. Recombinant tissue plasminogen activator (alteplase) for restoration of flow in occluded central venous access devices: a double-blind placebo-controlled trial--the Cardiovascular Thrombolytic to Open Occluded Lines (COOL) efficacy trial. Recombinant urokinase for restoration of patency in occluded central venous access devices. A double-blind, placebo-controlled trial. A prospective randomized trial of urokinase as an adjuvant in the treatment of proven Hickman catheter sepsis. Low-dose urokinase infusions to treat fibrinous obstruction of venous access devices in cancer patients. Recombinant tissue plasminogen activator versus urokinase for local thrombolysis of femoropopliteal occlusions: a prospective, randomized multicenter trial. Peripheral artery occlusion: treatment with abciximab plus urokinase versus with urokinase alone--a randomized pilot trial (the PROMPT Study). Platelet Receptor Antibodies in Order to Manage Peripheral Artery Thrombosis.
Recombinant urokinase (r-UK) is a high-molecular-weight urokinase produced in transfected, non-human, mammalian cells. A Phase II, randomized, double-blind, parallel, placebo-controlled, dose-ranging study was performed to compare the safety and efficacy of one or two instillations of three intraluminal concentrations of r-UK (5,000; 15,000; and 25,000 IU/mL) with a placebo for reestablishment of total function to occluded central venous access devices (CVADs).
                One-hundred eight patients with CVAD withdrawal or total occlusion were enrolled and randomized to treatment; 104 patients received at least one instillation of study drug and 101 patients completed treatment. All but one patient had cancer.
                All three concentrations of r-UK were significantly superior to placebo in restoring total CVAD function (patency of all occluded lumens) after one or two instillations of study medication (25,000 IU/mL r-UK, 68% vs. placebo, 28% [P =.007]; 15,000 IU/mL r-UK, 69% vs. placebo, 24% [P =.004]; 5,000 IU/mL r-UK, 70% vs. placebo, 28% [P =.003]). Comparisons of the three r-UK concentrations indicated no difference after one or two instillations with regards to patency restoration. Treatment-emergent hemorrhagic events occurring within 72 hours after study drug exposure were experienced by four patients (17%) in the 25,000 IU/mL r-UK group, two patients (7%) in the 15,000 IU/mL r-UK group, no patients in the 5,000 IU/mL r-UK group, and no patients in the placebo group.
                Efficacy and safety results of this study support further evaluation of a 5,000 IU/mL concentration of r-UK for treatment of occluded CVADs in adult and pediatric patients from 1 year of age. Central venous access devices (CVADs) are a mainstay of current medical therapy but often become occluded by thrombus. Tissue plasminogen activator (alteplase), at a dose of 2 mg per 2 mL, has been shown to be effective in restoring flow to catheters proven by radiographic contrast injection to be occluded by thrombus. The purpose of this double-blind placebo-controlled multicenter trial was to determine the efficacy of alteplase in occluded catheters without earlier contrast injections or radiographic examinations.
                Patients were eligible for inclusion if blood could not be withdrawn from their catheter after a period of normal function of at least 48 hours. Single or multiple catheters, peripherally inserted central catheters, catheters with valves, and implanted ports were eligible; catheters used for hemodialysis were not included. Patients were randomly assigned to one of two groups. In one group, patients received a first dose of 2 mg alteplase followed, if needed, by a second dose of 2 mg alteplase and a third dose of placebo. The other group received placebo first followed by one 2-mg dose of alteplase and then a second, if needed. Each dose was allowed to dwell for 2 hours and ability to withdraw blood from the catheter was reassessed. The endpoint was restoration of the ability to withdraw and infuse through the catheter. One hundred forty-nine patients were randomized: 74 received placebo first, 75 received alteplase first.
                After the first 2-hour treatment, function was restored to 74% in the alteplase arm and 17% in the placebo arm (P <.0001 compared to placebo). After one or two treatments, function was restored in 90% of patients. There were no serious study-drug-related adverse events, no intracranial hemorrhage, no major hemorrhage, and no embolic events.
                Infusion of alteplase appeared to be safe and effective in restoring flow to occluded catheters without need for pretreatment radiographic evaluation. The interval occlusion of central venous access devices (CVADs) remains a significant clinical problem, often requiring re-intervention for catheter exchange or replacement. The purpose of this Phase 3, multi-center, double-blinded study was to test the hypothesis that instillation of recombinant urokinase (r-UK) 5000 IU/ml is superior to placebo in restoring total catheter patency to an unselected cohort of occluded CVADs. After obtaining informed consent, adult and pediatric patients with occluded, non-hemodialysis CVADs of any duration or type were randomized (2 : 1) to receive either r-UK 5000 IU/ml or placebo instilled into all occluded lumens of their catheter. Catheter function was assessed at 5, 15 and 30 min after the first instillation. If the catheter remained occluded after 30 min, a second dose was instilled with repeat assessments at 5, 15 and 30 min. The primary efficacy variable was the restoration of catheter function to all treated lumens (i.e., total catheter patency) after one or two instillations. Catheters that were not successfully recanalized after two instillations were allowed to receive up to two instillations of open-label r-UK administered in the same manner. The primary safety variable was the occurrence of hemorrhagic and non-hemorrhagic events within 72 hr after instillation. A total of 180 patients were enrolled at 43 sites in the United States and Canada. Most patients were adults, although 20% were </=18 years of age. CVAD types included totally implanted subcutaneous ports (45%), PICC lines (26%), non-tunneled percutaneous catheters (18%), and tunneled percutaneous catheters (10%). All CVADs were occluded by virtue of their inability to withdraw blood (withdrawal occlusion). Additionally, 32% of catheters were completely dysfunctional as blood could not be withdrawn and fluids could not be infused (total occlusion). Analysis of the results showed that r-UK was significantly better than placebo in restoring catheter function (54% versus 30%, p = 0.002). There were no major hemorrhagic events within 72 hr after up to four r-UK instillations, and the incidence of non-hemorrhagic events was similar among the r-UK and placebo groups. In conclusion, r-UK is superior to placebo in restoring total catheter patency to occluded CVADs. In patients with occluded CVADs, intra-catheter thrombolysis can restore patency and may obviate the need for catheter replacement. Chronic vascular access catheters have become an important adjunct to the treatment of children with complex medical diseases, particularly malignancy. One of the major complications of chronic venous access devices is bacterial infection of the catheter site and bloodstream. Infusion of systemic antibiotics directly into the catheter has been the standard initial therapy with failure leading to catheter removal and replacement. It has been suggested by a number of investigators that the addition of urokinase as a thrombolytic agent to lyse any accumulated thrombus or fibrin would increase the successful catheter clearance by antibiotics. This study was designed as a prospective, randomized trial to compare treatment of children with positive catheter blood cultures with either antibiotics alone or in combination with urokinase 5,000 U boluses 12 and 24 hours after study entry.
                A total of 63 patients were entered in the study. Thirty-three received antibiotics and urokinase, and 30 received antibiotics alone.
                A total of 45 catheters (71%) were cleared of infection and salvaged. Treatment failures leading to catheter removal occurred in 9 of 33 in the experimental group and 9 of 30 in the control population (no significant difference).
                Urokinase could not be shown to act as an adjuvant in the clearance of infection from chronic central venous access catheters that had no evidence of clot or thrombus. This study required the performance of a dye study and excluded any patient with a known thrombus. This conclusion must therefore be limited to patients with no evidence of a clot or fibrin sheath. This study was undertaken to determine the role of low-dose urokinase infusions in treating fibrinous occlusions of venous access devices (VADs) in cancer patients.
                Forty-two patients with VAD occlusions refractory to routine urokinase instillations were documented by x-ray (cathetergram) to have fibrin sleeves at the catheter tips. They were randomized to receive infusions of either urokinase (40,000 U/h) or urokinase with heparin (320 U/h) through their catheters. After 1, 3, 6, and 12 hours of treatment, the function of the VADs was reassessed. Whenever the obstruction had been relieved, the infusion was stopped and a repeat cathetergram was performed. The status of the unoccluded catheters was followed to determine the longevity of the restored function.
                Twenty-one catheters were treated with urokinase alone and 21 with the combination of urokinase and heparin. In each group, 16 VADs opened within 12 hours of treatment and five did not. By actuarial analysis, the probability was only 0.28 that a reopened catheter would reocclude within 6 months.
                Low-dose urokinase infusions can restore function to the majority of catheters occluded by fibrin sleeves. Adding heparin to the urokinase does not enhance the efficacy of the infusions. The restored function often persists until the VADs are removed. To report the outcome of a prospective, randomized, open multicenter trial comparing (1) the effects of local thrombolysis with recombinant tissue plasminogen activator (rtPA) or urokinase (UK) and (2) 2 administration techniques.
                Two hundred thirty-four patients with thromboembolic occlusions in 223 native femoral or popliteal arteries (95%) and 11 bypass grafts (5%) were randomized to rtPA (n = 124) or UK (n = 110) administered either through an endhole catheter (Hess technique) in 81 patients or a microporous balloon catheter (Schneider technique) in 153 patients. When lysis was incomplete, additional catheter interventions were applied to achieve patency. Results were analyzed by fluoroscopy during intervention and by angiography evaluated by independent experts blinded to the methods applied.
                The only significant difference between rtPA and UK was found at the end of lysis using the Hess technique. Complete reperfusion (TIMI grade 3) was produced in 60% of patients by rtPA versus 37% by UK (p = 0.045). By both techniques TIMI grade 3 was achieved in 62% with rtPA and in 50% with UK (p = 0.18). Independent of delivery technique, thrombolytic agent, or additional catheter interventions, TIMI grade 3 was achieved in 81% and angiographic patency in 88%. Primary patency at 6 months was 66%, which was increased by secondary interventions to 75%. Major amputations were performed in 6%, all in patients with initial Fontaine stage III/IV ischemia.
                With local thrombolysis alone, rtPA appears to be more effective than UK; however, additional catheter interventions further improved patency, abolishing the difference between the lytic agents. To evaluate the combination of a platelet glycoprotein IIb/IIIa complex receptor inhibitor and urokinase for treatment of recent (<or=6 weeks) arterial occlusion of the legs.
                Seventy patients with lower extremity arterial occlusion of less than 6 weeks duration were randomly separated into two treatment groups: urokinase plus abciximab or urokinase plus placebo. Primary end points were the rate of major complications at 30 days after randomization and the rates of amputation-free survival and survival without open surgery or major amputation at follow-up of 90 days. Two readers unaware of the patients' treatment group assignments analyzed digital subtraction angiograms as they related to the study end points, with a final consensus reading.
                Thrombolysis relative to clot length was faster in the urokinase-plus-abciximab group (odds ratio, 0.52; 95% CI: 0.35, 0.76; P < .001). There were no procedure-related deaths or intracranial hemorrhages, but the rate of nonfatal major bleeding was higher with urokinase plus abciximab (four of 50 patients) than with urokinase alone (none of 20 patients; P = .32). At 90 days, amputation-free survival was 96% (48 of 50 patients) in the urokinase-plus-abciximab group compared with 80% (16 of 20 patients) in the urokinase alone group. The hazard ratio for the two Kaplan-Meier curves was 0.42 (95% CI: 0.16, 0.96; P = .04).
                In patients with lower extremity arterial occlusion who were undergoing urokinase thrombolysis, adjunctive abciximab treatment resulted in faster thrombus dissolution and improved amputation-free survival, despite an increase in major bleeding.
There is inadequate evidence to draw strong conclusions on the efficacy or safety of the drug interventions included in this review. There is some low quality evidence from a meta-analysis of two studies investigating urokinase (various strengths) and some very low evidence from two single studies investigating alteplase 2 mg/2 mL that suggest that these two drug interventions may be effective in treating withdrawal or total occlusion of CVC lumens caused by thrombosis. Further high quality, sufficiently powered research is still required to look at the efficacy and safety of urokinase, alteplase and other chemical, surgical and drug interventions for treating CVC lumen occlusion. Research studies which exclusively include child participants are especially warranted.