Intervention Review

You have free access to this content

Surgery versus thrombolysis for initial management of acute limb ischaemia

  1. David C Berridge1,*,
  2. David O Kessel2,
  3. Iain Robertson3

Editorial Group: Cochrane Peripheral Vascular Diseases Group

Published Online: 6 JUN 2013

Assessed as up-to-date: 21 MAR 2013

DOI: 10.1002/14651858.CD002784.pub2


How to Cite

Berridge DC, Kessel DO, Robertson I. Surgery versus thrombolysis for initial management of acute limb ischaemia. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD002784. DOI: 10.1002/14651858.CD002784.pub2.

Author Information

  1. 1

    Leeds General Infirmary, Leeds Vascular Institute, Leeds, Yorkshire, UK

  2. 2

    Leeds Teaching Hospitals Trust, Department of Clinical Radiology, Leeds, West Yorkshire, UK

  3. 3

    Gartnavel General Hospital, Department of Radiology, Glasgow, UK

*David C Berridge, Leeds Vascular Institute, Leeds General Infirmary, Great George Street, Leeds, Yorkshire, LS1 3 EX, UK. david.berridge@leedsth.nhs.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 6 JUN 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Nilsson 1992

MethodsStudy design: RCT.

Method of randomisation: Not stated.

Concealment of allocation: Unblinded.

Intention to treat: No.

Exclusions post randomisation: None.

Lost to follow up: 1.


ParticipantsCountry: Sweden.

No. of pats: 20.

Gender: 13 men, 7 women.

Mean age (years): 74 (range 45 to 91).

Inclusion criteria:
Duration of ischaemia requiring intervention > 24 hours < 14 days.

Exclusion criteria: Systolic BP higher than 200 mmHg, stroke within past 6 months, surgery within past 3 weeks, history of gastrointestinal bleeding, bleeding diathesis, know active peptic ulcer or current treatment with oral anticoagulants.


Interventions1) Surgery: balloon thromboembolectomy (n = 9)

2) Thrombolysis: 30 mg rt-PA over 3 hours with catheter advancement (n = 11).


OutcomesFollow up at 30 days:
revascularisation; failure of lysis; amputation; ankle/brachial pressure index.


NotesNo use of Fontaine or Rutherford classification of severity of ischaemia.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Ouriel 1994

MethodsStudy design: RCT.

Method of randomisation: Concealed computer generated randomisation cards opened at time of entry into study.

Concealment of allocation: Unblinded.

Intention to treat: Yes.

Exclusions post randomisation: Not stated.

Lost to follow up: Not stated.


ParticipantsCountry: USA.

No. of pats: 114 enrolled (57 surgery, 57 thrombolysis).

Gender: 25:32 surgery, 29:28 thrombolysis.

Mean age: 71 ± 1.7 years (surgery group); 69 ± 1.7 years (thrombolysis group).

Inclusion criteria: Limb threatening ischaemia of < 7 days duration (amputation deemed necessary without intervention), 18 years and older, embolic or thrombotic native arterial, autogenous bypass graft or prosthetic bypass graft.

Exclusion criteria: Mural thrombus found to be the cause of the occlusion (as confirmed by echocardiography), contraindication to thrombolytic therapy, major operative procedure within 14 days, active peptic ulcer disease, intracranial neoplasm, history of cerebrovascular accident, contraindication to operative revascularisation, nonambulatory or had a non-functional extremity prior to the ischaemic event, ischaemic process was deemed irreversible (Society for Vascular Surgery/International Society for Cardiovascular Surgery Class III), contraindication to arteriography present, including serum creatinine greater than 2.5 mg/dl or history of significant allergy to contrast agents, positive pregnancy test.


Interventions1) Surgical revascularisation or primary amputation if no outflow vessels.

2) Thrombolysis with urokinase: 4000 IU/min; 2000 IU/min after 2 hours; 1000 IU/min after 4 hours.


OutcomesFollow up at 12 months:
limb salvage; amputation; patency rate; duration of hospitalisation; event free survival; time to reperfusion; bleeding complications; death.


NotesUsed Rutherford classification of critical ischaemia.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Ouriel 1996

MethodsStudy design: RCT.

Method of randomisation: Concealed telephone randomisation at time of entry into study.

Concealment of allocation: Unblinded.

Intention to treat: Yes.

Exclusions post randomisation: 4

Lost to follow up: Not stated.


ParticipantsCountry: USA and Canada.

No. of pats: 217 recruited from 79 participating centres.

Gender (% male):
Surgery - 62.2
2000 IU/min - 70.7
4000 IU/min - 74.4
6000 IU/min - 76.1

Mean age (years):
Surgery - 66.5 ± 1.8
2000 IU/min - 66.2 ± 1.9
4000 IU/min - 62.2 ± 1.8
6000 IU/min - 62.5 ± 1.8

Inclusion criteria:
Threatened (Class II) severity limb ischaemia of < 14 days duration, occlusion confirmed with arteriography, native artery or bypass graft, 18 years or older, informed consent by able patient or surrogate, eligible for both operative and thrombolytic intervention.

Exclusion criteria: Profound ischaemia with permanent motor paresis or sensory loss, uncontrolled hypertension (systolic BP > 180, diastolic BP > 110 mm Hg), stroke within 6 months, TIA within 2 months, significant internal haemorrhage within 10 days, serious gastrointestinal haemorrhage within 14 days, biopsy of organs, puncture of incompressible vessel within 14 days, severe hepatic dysfunction, life expectancy less than 1 year.


Interventions1) Surgery including primary amputation (n = 58).

2) Thrombolysis with urokinase at 2000 IU/min (n = 48), or 4000 IU/min (n = 52), or 6000 IU/min (n = 55) for first 4 hours followed by 2000 IU/min thereafter for up to 48 hours.


OutcomesFollow up at 12 months:
arterial recanalisation and extent of clot lysis at 4 hours; amputation-free survival at 6 and 12 months.

Composite in-hospital outcome index (see notes):
reduction in severity of predicted intervention;
ankle/brachial pressure index.


NotesOrder of severity of interventions were compared from the initial predicted intervention to the actual intervention ultimately required by the time of initial hospital discharge.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Ouriel 1998a

MethodsStudy design: RCT.

Method of randomisation: Concealed telephone randomisation.

Concealment of allocation: Unblinded.

Intention to treat: Yes.

Exclusions post randomisation: 4

Lost to follow up: 17 thrombolysis group, 16 surgery group received no randomised treatment but were included in the intention to treat analysis.


ParticipantsCountry: USA and Northern Europe, 113 centres.

No. of pats: 548 recruited.

Gender: 192 men, 80 women thrombolysis group, 170 men, 102 women surgery group .

Mean age (years): 64.9 ± 0.78 thrombolysis group, 64.5 ± 0.78 surgery group.

Inclusion criteria: 14 days or less duration of reversible limb-threatening ischaemia; over 17 years of age, non-pregnant, suitable for either open surgical treatment or thrombolysis.

Exclusion criteria: pregnancy and women of child bearing age in whom pregnancy was a possibility.


Interventions1) Surgery, including angioplasty and primary amputation (n = 272).

2) Thrombolysis with urokinase: 4000 IU/min for 2 hours then 2000 IU/min for a maximum duration of 48 hours therapy (n = 272).


OutcomesFollow up at 6 and 12 months:
Amputation-free survival at 6 and 12 months; survival free of open surgical procedures at 6 months (lysis group); ankle/brachial pressure index; degree of clot lysis; rates of adverse effects of treatment, including haemorrhagic complications.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

STILE 1994

MethodsStudy design: RCT.

Method of randomisation: Concealed telephone randomisation.

Concealment of allocation: Unblinded.

Intention to treat: Yes and per protocol.

Exclusions post randomisation: 28 (16 surgery, 12 thrombolysis).

Lost to follow up: 4.


ParticipantsCountry: USA.

No. of pats: 392.

Gender: 268 men, 124 women.

Mean age: 62.5 years.

Inclusion criteria: Symptoms of worsening limb ischaemia over past 6 months requiring intervention, angiographically confirmed non embolic arterial or bypass graft, aged 18 to 90.

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 BO greater than 180 mmHg and diastolic BP greater than 110 mm Hg), 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 last 30 days.

Other criteria which the investigators had to exercise good clinical judgment 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, severe ischaemia which requires immediate surgical intervention.


Interventions1) Surgical revascularisation including primary amputation.

2) Thrombolysis - choice of lytic agent used chosen by investigators, either rt-PA 0.05 mg/kg/hr 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/hour titrated to maintain the APTT between 1.5 to 2.0 times the control, plus 325 mg aspirin at the time of randomisation and daily thereafter.


OutcomesFollow up at 6 months: Composite Clinical Outcome; ongoing or recurrent ischaemia; death or major amputation; life-threatening haemorrhage; 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.


NotesFor further details of 'Composite Clinical Outcome' see original paper
NOTE: Two further reports concerning 12 month data on native arteries and grafts from this study have been published as Weaver 1996 and Comerota 1996. These are discussed in the main body of the text in conjunction with the original paper.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Patel 1999Markov analysis of cost-effectiveness based on TOPAS database, but no actual prospective economic data collection was performed as part of the TOPAS trial itself.

Tiek 2009Non randomised controlled study.

 
Comparison 1. Surgery versus thrombolysis: Limb salvage

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Limb salvage at 30 days4636Peto Odds Ratio (Peto, Fixed, 95% CI)1.21 [0.74, 1.99]

 2 Limb salvage at 6 months2546Peto Odds Ratio (Peto, Fixed, 95% CI)0.86 [0.59, 1.26]

 3 Limb salvage at 1 year2654Peto Odds Ratio (Peto, Fixed, 95% CI)0.88 [0.62, 1.23]

 
Comparison 2. Surgery versus thrombolysis: Amputation

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Amputation at 30 days3615Peto Odds Ratio (Peto, Fixed, 95% CI)0.97 [0.51, 1.85]

 2 Amputation at 6 months1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

 3 Amputation at 1 year3768Peto Odds Ratio (Peto, Fixed, 95% CI)1.13 [0.82, 1.55]

 
Comparison 3. Surgery versus thrombolysis: Death

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Death at 30 days4636Peto Odds Ratio (Peto, Fixed, 95% CI)0.58 [0.30, 1.13]

 2 Death at 6 months1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

 3 Death at 1 year3768Peto Odds Ratio (Peto, Fixed, 95% CI)0.87 [0.61, 1.25]

 
Comparison 4. Surgery versus thrombolysis: Vessel patency

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Vessel patency at 30 days1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

 
Comparison 5. Surgery versus thrombolysis: Stroke

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Stroke at 30 days51180Peto Odds Ratio (Peto, Fixed, 95% CI)6.41 [1.57, 26.22]

 
Comparison 6. Surgery versus thrombolysis: Major haemorrhage

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Major haemorrhage at 30 days41070Peto Odds Ratio (Peto, Fixed, 95% CI)2.80 [1.70, 4.60]

 
Comparison 7. Surgery versus thrombolysis: Distal embolization

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Distal embolization at 30 days3678Peto Odds Ratio (Peto, Fixed, 95% CI)8.35 [4.47, 15.58]

 
Comparison 8. Surgery versus thrombolysis: Reduction in level of surgery required

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Reduction in level of surgery required at 30 days31046Peto Odds Ratio (Peto, Fixed, 95% CI)5.37 [3.99, 7.22]

 2 Reduction in need for open surgery at 6 months1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

 
Comparison 9. Surgery versus thrombolysis: Combined amputation / death

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Combined amputation / death at 6 months in less than 14 days ischaemia1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

 
Comparison 10. Surgery versus thrombolysis: Continuous ischaemia at 1 year

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Native vessels1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

 2 Bypass grafts1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected