Summary

The interval occlusion of central venous access devices(CVADs) remains a significant clinical problem, often requiringre-intervention for catheter exchange or replacement.The purposeof this Phase 3, multi-center, double-blinded study was totest the hypothesis that instillation of recombinant urokinase(r-UK) 5000 IU/ml is superior to placebo in restoring totalcatheter patency to an unselected cohort of occluded CVADs.After obtaining informed consent, adult and pediatric patientswith occluded, non-hemodialysis CVADs of any duration ortype were randomized (2 : 1) to receive either r-UK 5000 IU/mlor placebo instilled into all occluded lumens of their catheter.Catheter function was assessed at 5, 15 and 30 min after thefirst instillation. If the catheter remained occluded after 30 min,a second dose was instilled with repeat assessments at 5, 15and 30 min.The primary efficacy variable was the restoration ofcatheter function to all treated lumens (i.e., total catheterpatency) after one or two instillations. Catheters that were notsuccessfully recanalized after two instillations were allowed toreceive up to two instillations of open-label r-UK administeredin the same manner.The primary safety variable was the occur- rence of hemorrhagic and non-hemorrhagic events within 72 hrafter instillation. A total of 180 patients were enrolled at 43sites in the United States and Canada. Most patients wereadults, although 20% were =18 years of age.CVAD types includedtotally implanted subcutaneous ports (45%), PICC lines(26%), non-tunneled percutaneous catheters (18%), and tunneledpercutaneous catheters (10%). All CVADs were occludedby virtue of their inability to withdraw blood (withdrawalocclusion). Additionally, 32% of catheters were completely dysfunctionalas blood could not be withdrawn and fluids could notbe infused (total occlusion). Analysis of the results showed thatr-UK was significantly better than placebo in restoring catheterfunction (54% versus 30%, p = 0.002). There were no majorhemorrhagic events within 72 hr after up to four r-UK instillations,and the incidence of non-hemorrhagic events was similaramong the r-UK and placebo groups. In conclusion, r-UK issuperior to placebo in restoring total catheter patency tooccluded CVADs. In patients with occluded CVADs, intra-catheterthrombolysis can restore patency and may obviate theneed for catheter replacement.