Intervention Review

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Fibrinolytic agents for peripheral arterial occlusion

  1. Iain Robertson1,*,
  2. David O Kessel2,
  3. David C Berridge3

Editorial Group: Cochrane Vascular Group

Published Online: 19 DEC 2013

Assessed as up-to-date: 21 MAR 2013

DOI: 10.1002/14651858.CD001099.pub3


How to Cite

Robertson I, Kessel DO, Berridge DC. Fibrinolytic agents for peripheral arterial occlusion. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD001099. DOI: 10.1002/14651858.CD001099.pub3.

Author Information

  1. 1

    Gartnavel General Hospital, Department of Radiology, Glasgow, UK

  2. 2

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

  3. 3

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

*Iain Robertson, Department of Radiology, Gartnavel General Hospital, 1053 Great Western Road, Glasgow, G12 0XN, UK. itsiainhi@gmail.com. Iain.Robertson2@ggc.scot.nhs.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 19 DEC 2013

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Characteristics of included studies [ordered by study ID]
Berridge 1991

MethodsStudy design: RCT parallel group.


ParticipantsCountry: United Kingdom.

Setting: hospital.

No of patients: 60; 20 i.v. rt-PA, 20 i.a. SK, 20 i.a. rt-PA.

Mean age: 71 years.

Gender: 39 M; 21 F.

Inclusion criteria: peripheral lower limb ischaemia <30 days duration.

Exclusion criteria: clinically apparent arterial emboli treated with surgical embolectomy.


InterventionsTreatment: 3 infusion protocols.

(i) i.a. streptokinase infused at 5000 U/hr with 250 U/hr heparin (20pts);
(ii) i.a rt-PA 0.5 mg/hr with 250 U/hr heparin;
(iii) i.v. rt-PA max total dose 100 mg rt-PA at 4 rates of infusion 1, 2, 5 and 10 mg/hr.

Duration of treatment: complete lysis achieved or patient deterioration or lytic stagnation after a 12 hr period.

Follow up: 30 days and 3 months.


OutcomesPrimary: limb salvage, amputation, death.

Secondary: death, major haemorrhage.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom number generator.

Allocation concealment (selection bias)Unclear riskInformation on allocation concealment not provided.

Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskExclusions post-randomisation: 6 not included in the analysis.

Lost to follow up: none.

Selective reporting (reporting bias)Low riskAll outcomes reported.

Other biasUnclear riskStudy financially supported by Boehringer Ingelheim who supplied recombinant tissue plasminogen activator.

Mahler 2001

MethodsStudy design: prospective RCT.


ParticipantsCountry: Germany and Switzerland.

Setting: hospital.

No of patients: 234.

Mean age: 69.5 years rt-PA; 70.1 years UK.

Gender: M 81 (65%) rt-PA; M 64 (58%) UK.

Inclusion criteria: angiographically documented thrombotic or embolic occlusions five to 40 cm length.

Exclusion criteria: thrombi > 6 months old or emboli > 6 weeks. Standard exclusions for increased bleeding risk from thrombolysis.


Interventions(i) rt-PA;

(ii) UK;

Either end hole catheter or microporous balloon.

End hole catheter 2.5 mg/hr rt-PA or 100,000 IU/hr UK.

Microporous balloon 0.5 mg/cm thrombus length rt-PA or 20,000 IU/cm thrombus length.

Duration of treatment: end hole catheter serially advanced. Microporous balloon one hour if complete lysis not achieved then infusion lysis and secondary intervention.

Follow up: end of lysis and at six months; 81% reached six month follow up.


OutcomesPrimary: vessel patency, time to lysis, amputation, death.

Secondary: complications including bleeding and cerebral haemorrhage.


NotesTechniques not randomised - dependant on local practice - but use of rt-PA or UK was randomised. Complex trial as two infusion techniques used; the microporous balloon more rapid pharmacomechanical action but no difference in outcomes by technique or drug at follow up.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomised in blocks of 10.

Allocation concealment (selection bias)Unclear riskMethod not stated.

Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk55 patients lost to follow up but no information on statistical handling of missing data.

Exclusion post-randomisation: none recorded.

Selective reporting (reporting bias)Low riskAll primary and secondary outcomes reported.

Other biasUnclear riskSupported by a grant from Boehringer Ingelheim who manufactured the Alteplase.

Meyerovitz 1990

MethodsStudy design: RCT.


ParticipantsCountry: USA.

Setting: hospital.

No of patients: 32.

Mean age: 58 years.

Gender: 22 M and 10 F.

Inclusion criteria: native/bypass occlusion < 90.

Exclusion criteria: standard exclusions for increased bleeding risk from thrombolysis.


Interventions(i) rt-PA 10 mg intrathrombic dose then 5 mg/hr up to 24 hours.

(ii) UK dose 60,000 IU intrathrombic bolus and 240,000 IU/h for two hrs, 120,000 IU/h for two hrs and 60,000 IU for up to 20 hours.

Duration of treatment: 24 hours.

Follow up: end of lysis for degree of lysis and surgery, angioplasty, death, limb loss within 30 days.


OutcomesPrimary: 95% lysis and restoration of flow, time to lysis.

Secondary: surgery, angioplasty, death, limb loss within 30 days, blood transfusion (major haemorrhage) within 72 hours.


NotesLysis continued for 18 to 72 hours in 6 urokinase (4 successful).
Lysis continued for 2 pts with urokinase who received rt-PA unsuccessfully.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised by means of consecutive numbers.

Allocation concealment (selection bias)Unclear riskSealed envelopes.

Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskExclusions post-randomisation: none recorded.

No losses to follow up.

Selective reporting (reporting bias)Low riskAll outcomes reported.

Other biasUnclear riskSupported in part by Genentech Inc (Activase manufacturer) and Abbott Laboratories (Abbokinase manufacturer).

Ouriel 1999

MethodsPhase II randomised, multicentre double blind study.


ParticipantsCountry: USA.

Setting: hospital.

No of patients: 241.

Mean age: 65.1 years.

Gender: M 143 (62.7%); F 85 (37.3%).

Inclusion criteria: patients with lower extremity native artery or graft occlusion of less than or equal to 14 days duration.

Exclusion criteria: standard exclusions for increased bleeding risk from thrombolysis.


Interventions(i) pro-urokinase 2 mg, 4 mg, 8 mg/hr for 8 hours followed by 0.5 mg/hr in each group.

(ii) urokinase group 4000 IU/min for 4 hours followed by 2000 IU/min. Thrombus lacing dose based on length of occlusion.

Duration of treatment: > 95% clot lysis or 24 hours.

Follow up: 30 days.


OutcomesPrimary: vessel patency, time to lysis, dose of study drug, amputation, death.

Secondary: complications including bleeding.


NotesDose response curve for pro-urokinase derived. Fibrin specificity of prourokinase lost at equipotent doses with urokinase.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation was stratified by type of occlusion; native artery or bypass graft.

Allocation concealment (selection bias)Unclear riskMethod not stated.

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll analyses based on participants who received their randomised treatment. Of 241 patients randomised 13 patients were entered into the trial but never received the specified therapy (reasons given). No losses to follow up recorded.

Selective reporting (reporting bias)Low riskAll outcomes reported.

Other biasUnclear riskSome authors were affiliated to Abbott Laboratories manufacturers of Abbokinase.

Schweizer 1996

MethodsStudy design: RCT.


ParticipantsCountry: Germany.

Setting: hospital.

No of patients: 120; 60 rt-PA, 60 UK.

Mean age: 65 years.

Gender: M 60%, F 40% UK; M 57%, F 43% rt-PA.

Inclusion criteria: < 3 months occlusion of femoropopliteal segment.

Exclusion criteria: not recorded.


Interventions(i) rt-PA 5 mg intrathrombic bolus followed by infusion at 5 mg/hr plus heparin 750 IU/hr.
(ii) urokinase 60,000 IU/hr plus heparin 700 IU/hr.

Treatment duration: rt-PA 1 to 4 hrs (mean 2 hrs); UK 6 to 72 hrs (mean 24 hours).

Follow up: 6 months follow up.


OutcomesPrimary: amputation, Fontaine, ABPI, vessel patency.

Secondary: death.


NotesFontaine IIb claudication 49% of study population. Short occlusion lengths 6 cm.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStates randomised but method not given.

Allocation concealment (selection bias)Unclear riskNot stated.

Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskExclusions post-randomisation: none recorded.

Two patients lost to follow-up but no information on statistical handling of missing data.

Selective reporting (reporting bias)Low riskAll outcomes reported.

Other biasUnclear riskNo declarations of interest stated, no information given regarding sponsorship.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Braithwaite 1997Comparison of dose regimes for high and low dose rt-PA

Cina 1999Comparison of rt-Pa versus urokinase but non-randomised selection by surgeons preference

Dawson 1991Non-randomised streptokinase vs rt-PA

Dawson 1991aNon-randomised

Didier 1995Comparison of angioplasty versus rt-PA and angioplasty

Dube 1996Only partially randomised 10 of 40 patients; insufficient for analysis

Duda 2001Not a true comparison of agents; use of abxicimab as an adjunctive agent studied. Complex randomisation 5:2 to support complication rate as major finding may have impact on study findings

Gryglewski 1995Not a comparison of thrombolytic agents

Han 2010Paper reports NAPA II/III trials. Not a comparison of thrombolytic agents - comparison with placebo. Safety and efficacy trial with primary end point of avoidance of open vascular surgery within 30 days of treatment

Hess 1996Non-comparative and non-randomised

Hiatt 2002Not a comparison of agents

Reichle 1976Randomised but 11 patients in one group and 6 in the other group - method of randomisation not stated, clinical enrolment criteria not accurately described

Sarif 2005Not arterial thrombolysis

Schulman 1996Venous thromboembolism

STILE 1994Subset of patients comparing urokinase and rt-PA but insufficient detail reported to permit analysis. Authors report no difference between rt-PA and urokinase

Tepe 2006Comparison is of the effect of the addition of abxicimab to thrombolytic agents and not a true comparison of agents. More appropriately considered under infusion techniques

Vanderschueren 1995Staphylokinase. Pilot study. No apparent randomisation. Not blinded. No control group - study compared two different infusion protocols

Wen 2005Comparison of urokinase and danshen root

 
Comparison 1. Intra-arterial streptokinase versus intravenous rt-PA

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

 1 Vessel Patency immediately post lysis1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 Asymptomatic Limb salvage at 30 days1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 3 Amputation at 30 days1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 4 Death1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 5 Complications- major haemorrhage1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 6 Complications- minor haemorrhage1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 2. Intra-arterial streptokinase versus intra-arterial rt-PA

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

 1 Vessel patency immediately post lysis1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 Asymptomatic Limb salvage at 30 days1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 3 Amputation at 30 days1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 4 Death1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 5 Complications- major haemorrhage1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 6 Complications- minor haemorrhage1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 3. Intra-arterial urokinase versus intra-arterial rt-PA

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

 1 Vessel patency immediately post lysis3Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 Limb salvage3368Odds Ratio (M-H, Fixed, 95% CI)1.68 [0.68, 4.15]

 3 Major amputation at 30 days-6 months3Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 4 Death3368Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.24, 2.54]

 5 Complications - major haemorrhage3298Odds Ratio (M-H, Fixed, 95% CI)0.68 [0.19, 2.40]

 6 Complications - minor haemorrhage3386Odds Ratio (M-H, Fixed, 95% CI)0.50 [0.20, 1.26]