Purpose: Thrombolytic therapy is widely used in the treatment of peripheral arterial occlusion, but prospective, randomized comparisons with standard therapy remain few. A multicenter trial of thrombolysis or peripheral arterial surgery (TOPAS) was organized to compare critically the use of recombinant urokinase (rUK) or surgery for the initial treatment of acute lower-extremity ischemia. Phase I of the trial was designed as a dose-ranging trial to evaluate the safety and efficacy of three doses of rUK in comparison with surgery.
Methods: In a multicenter, prospective, double-blind comparison, 213 patients who had acute lower-extremity ischemia for 14 days or fewer were randomized to one of two groups. The first group received one of three dosages of rUK (catheter-directed at 2000, 4000, or 6000 IU/min for 4 hours, then 2000 IU/min to a maximum of 48 hours). The second group underwent surgery. Successful thrombolysis was followed by surgical or endovascular interventions when anatomic lesions responsible for the occlusion were unmasked. Patients were followed-up for 1 year; data were evaluated on an intent-to-treat basis.
Results: The 4000 IU/min rUK dosage was chosen as the most appropriate thrombolytic regimen because it maximized lytic efficacy against the risk of bleeding. Complete (> 95%) lysis of thrombus was achieved in 71% of the 49 patients who were randomized to the 4000 IU/min group, with a mean infusion time of 23 hours. In contrast, complete lysis was achieved in 67% of patients who received 2000 IU/min and in 60% of patients who received 6000 IU/min. Hemorrhagic complications occurred in 2% of the 4000 IU/min group versus 13% of the 2000 IU/min group (p = 0.05) and 16% of the 6000 IU/min group (p = 0.03). In a comparison of the 4000 IU/min group with the surgical group, the 1-year mortality rate (14% vs 16%) or amputation-free survival rate (75% vs 65%) did not differ significantly. The frequency and magnitude of surgery in the patients randomized to rUK were decreased (p < 0.001).
Conclusion: The preliminary results suggest that an initial rUK dose of 4000 IU/min is safe and efficacious in the treatment of acute lower-extremity ischemia. rUK therapy is associated with limb salvage and patient survival rates similar to those achieved with surgery, concurrent with a reduced requirement for complex surgery after thrombolytic intervention.