Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial.

PURPOSE

This study was designed to evaluate intra-arterial thrombolytic therapy as part of a treatment strategy for patients requiring revascularization for lower limb ischemia caused by nonembolic arterial and graft occlusion.

MATERIALS AND METHODS

Patients with native arterial or bypass graft occlusion were randomized prospectively to either optimal surgical procedure or intra-arterial, catheter-directed thrombolysis with recombinant tissue plasminogen activator (rt-PA) or urokinase (UK). Thrombolysis patients required successful catheter placement into the occlusion before infusion of either rt-PA at 0.05 mg/kg/hr for up to 12 hours or UK of 250,000 units bolus followed by 4000 units/min x 4 hours, then 2000 units/min for up to 36 hours. A composite clinical outcome of death, ongoing/recurrent ischemia, major amputation, and major morbidity was the primary endpoint. Additional endpoints were reduction in surgical procedure, clinical outcome classification, length of hospitalization, and outcome by duration of ischemia.

RESULTS

Randomization was terminated at 393 patients because a significant primary endpoint occurred by the first interim analysis. Failure of catheter placement occurred in 28% of patients who were randomized to lysis, and thus, were considered treatment failures. Thirty-day outcomes demonstrated significant benefit to surgical therapy compared with thrombolysis (p < 0.001), primarily because of a reduction in ongoing/recurrent ischemia (p < 0.001). However, clinical outcome classification at 30 days was similar. Stratification by duration of ischemia indicated that patients with ischemic deterioration of 0 to 14 days had lower amputation rates with thrombolysis (p = 0.052) and shorter hospital stays (p < 0.04). Patients with ischemic deterioration of > 14 days who who were treated surgically had less ongoing/recurrent ischemia (p < 0.001) and trends toward lower morbidity (p = 0.1). At 6-month follow-up, there was improved amputation-free survival in acutely ischemic patients treated with thrombolysis (p = 0.01); however, chronically ischemic patients who were treated surgically had significantly lower major amputations rates (p = 0.01). More than half of thrombolysis patients (55.8%) had a reduction in magnitude of their surgical procedure (p < 0.001). There was no difference in efficacy or safety between rt-PA and UK; however, in the thrombolysis group as a whole, fibrinogen depletion predicted hemorrhagic complications (p < 0.01).

CONCLUSIONS

Surgical revascularization of patients with < 6 months of ischemia is more effective and safer than catheter-directed thrombolysis. Although ongoing/recurrent ischemia is greater in the patients undergoing thrombolysis, 30-day clinical outcomes are similar, probably because of cross-over treatment to surgery. There is no difference in efficacy or safety between rt-PA and UK, although bleeding occurs in patients with greater fibrinogen depletion. A significant reduction in planned surgical procedure is observed after thrombolysis. Patients with acute ischemia (0-14 days) who were treated with thrombolysis had improved amputation-free survival and shorter hospital stays. However, for patients with chronic ischemia (> 14 days), surgical revascularization was more effective and safer than thrombolysis. Combining a treatment strategy of catheter-directed thrombolysis for acute limb ischemia with surgical revascularization for chronic limb ischemia offers the best overall results.