STILE Trial.

Methods	Study design: randomised, not blinded Method of randomisation: randomised by telephone and stratified for native artery occlusions, bypass graft occlusions, or unreconstructable vascular disease; randomised into three groups to test two different methods of thrombolysis; analysed as intention‐to‐treat
Participants	Country: USA and Canada. Number of participants: 237 Sex: males and females Age: median age 66 years (80 participants with IC, 83 with rest pain and 74 with ischaemic necrosis) Inclusion criteria: individuals aged 18 to 90 years with signs or symptoms of worsening limb ischaemia within the past 6 months requiring intervention, and those with angiographically documented nonembolic arterial occlusion Exclusion criteria: individuals with acute embolism, active internal bleeding, or a history of cerebrovascular accident, intracranial bleed, transient ischaemic attack, recent intracranial or intraspinal surgery or trauma, central nervous system neoplasm, arterio‐venous malformation or aneurysm, severe bleeding diathesis, uncontrolled hypertension, suspected pregnancy, recent eye surgery, contraindication to surgery
Interventions	Treatment: optimal surgical revascularization as determined by attending surgeon and documented before randomisation (86% had a bypass graft); autogenous material was used for infra‐inguinal occlusions, and prosthetics grafts for aorto‐iliac or ilio‐femoral occlusions Control: thrombolysis using either rt‐PA at 0.05 mg/kg/hr for up to 12 hours (56%); or urokinase as a bolus of 250,000 units followed by 4000 units/min for 4 hours, then 2000 units/min for 36 hours (44%) Duration: 1 year
Outcomes	Mortality Treatment failure Complications of surgery/intervention Primary patency Amputation rate
Notes	This trial has been included with the following reservations: participants with native artery disease were a subset of a larger study that included individuals with graft occlusion (total number 393), although the stratified randomisation should have balanced native arterial disease with graft disease; only 86% had bypass grafts, and presumably the remainder underwent thrombectomy or thromboendarterectomy; and 20% of the participants had acute (less than 14 days) ischaemia. This study was supported by a research grant from Genentech, Inc., South San Francisco, California.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information of method of randomisation provided.
Allocation concealment (selection bias)	Low risk	Quote: "The investigators and study coordinators telephoned a 24‐hour/day, 7‐day/week randomization center". Comment: Appropriate method of allocation concealment.
Blinding (performance bias and detection bias) All outcomes	Low risk	See below.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	No information provided, but most probably no blinding obtained given the nature of interventions.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	No information, but probably no blinding existed. However, the outcome and the outcome measurement were not likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "A detailed case report form was completed for each patient. The accuracy of the case report forms were verified by study monitors, who checked them with the patients' medical records. The case report forms then were forwarded to the data coordinating center (Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina, Chapel Hill, NC) for evaluation and the generation of queries about missing or inconsistent data and subsequent data entry". Comment: Transparent process of dealing with missing or incomplete data.
Selective reporting (reporting bias)	Low risk	Study protocol available and all prespecified outcomes reported.
Other bias	Unclear risk	The 237 participants with native artery disease were a subset of a larger trial of 393 participant, which included both native artery and graft disease which may have biased the results.