STILE 1994.

Methods	Study design: randomised controlled trial Intention‐to‐treat analysis: yes Country: USA (31 centres)
Participants	Number randomised: total N = 393 (thrombolysis (rt‐PA n = 137; urokinase n = 112); surgery n = 144) Exclusions post randomisation: total N = 28 (thrombolysis n = 12; surgery n = 16) Losses to follow‐up: 4 Gender M/F: thrombolysis: rt‐PA 93/43; urokinase 70/42; surgery 105/39 Mean age, years: thrombolysis: rt‐PA 65.4; urokinase 64.9; surgery 65.3 Inclusion criteria: symptoms of worsening limb ischaemia over past 6 months requiring intervention, angiographically confirmed non‐embolic arterial or bypass graft, 18 to 90 years of age Exclusion criteria: infected peripheral arterial bypass grafts, previous enrolment in this trial, acute embolic occlusion, active internal bleeding, history of any cerebrovascular accident or intracranial bleeding, history of any TIA, intracranial or intraspinal surgery or trauma within past 2 months, any central nervous system neoplasm or aneurysm, known severe bleeding diathesis, severe uncontrolled hypertension (systolic BP > 180 mmHg and diastolic BP > 110 mmHg), known or suspected pregnancy or child‐bearing potential, eye surgery within past 3 months, inability to undergo surgical procedure (e.g. contraindication to general anaesthetic), severe cardiac disease, recent puncture of non‐compressible vessel, participation in another research protocol within the past 30 days; other criteria for which investigators had to exercise good clinical judgement included recent vascular surgery, major non‐vascular surgery within 10 days, significant liver dysfunction, history of internal bleeding or other significant bleeding within past 10 days, high likelihood of left heart thrombus, acute pericarditis or subacute bacterial endocarditis, trauma within past 10 days, asymptomatic cerebrovascular disease, diabetic or haemorrhage retinopathy, haemostatic defects, low platelet count, septic thrombophlebitis or occluded AV cannula at a seriously infected site, any other condition in which bleeding is a significant hazard, and severe ischaemia that requires immediate surgical intervention
Interventions	Thrombolysis: lytic agent used chosen by investigators ‐ either rt‐PA 0.05 mg/kg/h for up to 12 hours (max dose 200 mg) or urokinase 250,000‐IU bolus followed by 4000 IU/min for 4 hours, then 2000 IU/min for up to 36 hours. In addition, participants in the thrombolysis group received 5000 IU heparin as an intravenous bolus at the time of thrombolysis followed by 1000 U/h titrated to maintain APTT between 1.5 and 2.0 times control, plus 325 mg aspirin at the time of randomisation and daily thereafter Surgical revascularisation including primary amputation
Outcomes	Follow‐up at 6 months Composite clinical outcome, ongoing or recurrent ischaemia, death or major amputation (above‐knee or below‐knee), life‐threatening haemorrhage or stroke (hypotension requiring resuscitation), perioperative complications, renal failure requiring dialysis, serious anaesthesia‐related complications, vascular complications, post‐interventional wound complications, clinical improvement and reduction in surgery, patency and perfusion status, duration of ischaemia, length of hospitalisation
Notes	One of the major criticisms of the STILE publications is that the less than 14 days or more than 14 days analysis was a post hoc arbitrary division ‐ not a stratified part of the original protocol. Over 80% of all participants had a more than 14 days duration of symptoms before intervention. Study was supported by a grant from Genetech, Inc., San Francisco, California, USA
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Study utilised a centralised randomisation centre, which was contacted at the time of patient consent via telephone. Participants were stratified by whether occlusion involved native artery or bypass graft
Allocation concealment (selection bias)	Low risk	Study utilised a centralised randomisation centre, which was contacted at the time of patient consent via telephone
Blinding of participants and personnel (performance bias) All outcomes	High risk	Steps taken to blind participants to treatment were not described. Owing to the nature of the treatment, it would be very difficult to blind participants or personnel to treatment
Blinding of outcome assessment (detection bias) All outcomes	High risk	Steps taken to blind personnel to treatment were not described
Incomplete outcome data (attrition bias) All outcomes	Low risk	Study utilised an intention‐to‐treat analysis, but it should be noted that for 1‐year outcomes, results were given in 2 reports: 1 focussing on native artery occlusions, and the other on bypass graft occlusions; the former mentioned report included 261 participants, and the original report included 268 participants, with bypass graft occlusions
Selective reporting (reporting bias)	Low risk	All outcomes were reported on
Other bias	Unclear risk	Reported that 1000 randomised participants were needed for adequate power, but only 393 were randomised Quote: "Failure of catheter placement occurred in 28% of patients who were randomized to lysis, and thus, were considered treatment failures"

ABI: ankle‐brachial index.
 APTT: activated partial thromboplastin time.
 AV: arteriovenous.
 BP: blood pressure.
 h: hour.
 IU/min: international units per minute.
 rt‐PA: recombinant tissue plasminogen activator.
 SD: standard deviation.
 TIA: transient ischaemic attack.