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A Comparison of Recombinant Urokinase With Vascular Surgery as Initial Treatment for Acute Arterial Occlusion of the Legs - TOPAS
Description:
The Thrombolysis or Peripheral Arterial Surgery (TOPAS) trial was a randomized, multicenter study designed to compare the efficacy and safety of catheter-administered urokinase and conventional open surgery as initial treatment in patients with acute peripheral arterial occlusion threatening the viability of the leg.
Hypothesis:
Initial thrombolytic therapy may be an effective treatment for acute arterial occlusion of the legs and may be associated with reduced need for open surgical procedures.
Study Design
Study Design:
Patients Enrolled: 544
Mean Follow Up: One year
Patient Populations:
To be eligible for the study, patients had to have had an acute thrombotic or embolic occlusion of a leg (native artery or bypass graft) within 14 days before randomization that met the guidelines for reversible limb-threatening ischemia. Patients had to be over 17 years of age and medically eligible for either thrombolytic or surgical intervention.
Exclusions:
Patients with contraindications to thrombolysis, and women who were pregnant or in whom pregnancy was a possibility
Primary Endpoints:
Amputation-free survival at six months
Secondary Endpoints:
Survival free of open surgical procedures at six months among patients in the urokinase group, amputation-free survival at one year, the degree of clot lysis and increase in ankle–brachial blood-pressure index, and the rates of adverse effects of treatment, including hemorrhagic complications
Drug/Procedures Used:
Patients were randomized to urokinase (n=272) or surgery (n=272). Urokinase was infused through an intra-arterial catheter at a rate of 4000 IU/min during an initial four-hour infusion period and at a rate of 2000/min thereafter; the infusion ports were placed within the thrombus whenever possible. Concurrent unfractionated heparin was also administered intravenously in 62 urokinase-treated patients. Infusions were stopped when lysis was complete, when no further progress was evident on arteriography, or after 48 hours of therapy. Successful urokinase therapy was generally followed by surgical or endovascular interventions if a suitable lesion was identified.
Concomitant Medications:
Subtherapeutic amounts of heparin, administered through the arterial sheath, were permitted in order to prevent pericatheter thrombosis; aspirin, initially mandatory, was also discontinued during thrombolysis.
Principal Findings:
The thrombolysis group had a significantly higher proportion of men (p=0.046), patients with hepatic and renal insufficiency (p=0.027), and patients with pain at rest at presentation (p=0.003). No significant differences were found between the groups with regard to the duration of symptoms or the nature, location, or length of the arterial occlusion.
At six months, the amputation-free survival rate was 71.8% in the urokinase group and 74.8% in the surgery group (p=0.43; 95% confidence interval [CI] for the difference between treatments, -10.5 to 4.5% points); the respective rates at one year were 65.0% and 69.9% (p=0.23; 95% CI -12.9 to 3.1% points).
There was no significant difference in the rates of amputation-free survival at discharge from the hospital (83.5% in the urokinase group and 88.6% in the surgery group, p=0.08). The mortality rates for the urokinase and surgery groups were 8.8% and 5.9%, respectively, at hospital discharge (p=0.19), 16.0% and 12.3% at six months (p=0.22), and 20.0% and 17.0% one year after randomization (p=0.39).
The ankle–brachial index rose significantly after treatment in both groups (p<0.001), with no difference between groups (p=0.23). At the end of six months, 31.5% of patients in the urokinase group had had only percutaneous procedures, as compared with 5.8% of the surgical patients (p<0.001). At six months, the surgery group had undergone 551 open operative procedures (excluding amputations), as compared with 315 in the thrombolysis group. During the initial hospitalization, 54% of the patients in the urokinase group and 91% of those in the surgery group required an open surgical procedure, underwent amputation, or died (p<0.001).
Major hemorrhagic complications occurred in 12.5% of patients in the urokinase group, as compared with 5.5% in the surgery group (p=0.005). There was a significant association between the coadministration of heparin and the risk of major bleeding (p=0.02). Intracranial hemorrhage occurred in 1.6% in the urokinase group and no instances of intracranial bleeding in the surgery group. Distal embolization occurred 41 times in 36 patients treated with urokinase.
Interpretation:
Among patients with acute peripheral limb-threatening arterial occlusion, treatment with an initial strategy of thrombolysis with urokinase compared with immediate surgery was not associated with a difference in amputation-free survival or mortality at six months or one year, but was associated with increased hemorrhagic complications.
References:
Ouriel K, Veith FJ, Sasahara AA. A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators. N Engl J Med 1998;338:1105-11.
Keywords: Thrombolytic Therapy, Pyridinolcarbamate, Urokinase-Type Plasminogen Activator, Ankle Brachial Index, Heparin, Fibrinolytic Agents, Lower Extremity, Peripheral Vascular Diseases, Renal Insufficiency, Intracranial Hemorrhages, Thrombosis, Survival Rate, Confidence Intervals
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