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Fibrinolytic agents for peripheral arterial occlusion

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

Editorial Group: Cochrane Peripheral Vascular Diseases 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

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Index terms

Peripheral arterial thrombolysis is the process of using fibrinolytic drugs to dissolve an occluding blood clot. Thrombolysis has become established as a useful tool in the management of acute peripheral arterial ischaemia. It is particularly useful for those cases of less than two weeks duration (STILE 1994). Although data from randomised controlled studies are not extensive, much has been learnt about indications, risks and benefits of thrombolysis. The initial selection of patients for thrombolysis or surgery is the subject of a separate Cochrane review (Berridge 2013) ). Peripheral arterial thrombolysis was originally performed using intravenous administration of the drug. Relatively high doses were used to achieve therapeutic levels at the site of arterial occlusion (blockage). Subsequently, low dose intra-thrombus infusion became popular. This aimed to achieve higher local drug concentrations for a smaller total dose. Success rates appeared much improved and complication rates became more acceptable. In an attempt to achieve faster thrombolysis, a high dose bolus (the initial dose) and forced injection techniques such as 'pulse spray' have been utilised. Infusion techniques for peripheral arterial thrombolysis are the subject of another Cochrane review (Kessel 2004). Overall, a relatively small number of thrombolytic agents have been used and compared within randomised controlled studies. More novel agents are starting to become available although the information to permit their role in clinical practice is currently very limited.

 

Description of the condition

Acute peripheral arterial ischaemia results from an abrupt reduction in blood flow to a limb. It is usually caused by a blood clot (thrombosis) which may form in a diseased artery or a bypass graft, or travel there from a remote site via the bloodstream. Clinical manifestations vary depending on the site and length of the occlusion. Relatively minor reductions in perfusion result in calf pain during exercise (intermittent claudication). More significant ischaemia leads to pain at rest. If flow is not promptly restored, this may lead to tissue death requiring amputation. Thrombolysis is less often used for pain during exercise (intermittent claudication) as treatment carries significant risks.

 

Description of the intervention

Peripheral arterial thrombolysis has become established as a useful adjunct to the management of peripheral arterial ischaemia and has been most useful for those cases of more recent onset, particularly within two weeks (STILE 1994). A number of fibrinolytic agents have been used for peripheral arterial thrombolysis. Streptokinase was the first agent described. Concern that repeated exposure led to significant antigenic reactions (immune responses) including anaphylaxis (a severe allergic reaction) has driven the search for alternative drugs. Urokinase (used in the USA) and rt-PA (used in the UK) have increasingly become established as the first line agents for peripheral arterial thrombolysis. Potential advantages of these agents include improved safety, greater efficacy and more rapid response. More recently, drugs such as pro-urokinase and recombinant staphylokinase have been introduced.

 

Why it is important to do this review

There is a considerable amount of literature on a wide variety of thrombolytic techniques and agents; however data from randomised trials are very limited. Relatively few trials have specifically considered the optimal agent for peripheral thrombolysis. Determination of the optimal agent is made more difficult because of variations in drug administration techniques as well as the drugs administered. The combination of available results, where appropriate, may allow clearer conclusions to be developed.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Index terms
 
Primary objective

To determine which is the most effective fibrinolytic agent for peripheral arterial thrombolysis. The logistics of the various techniques are discussed. The specific hypothesis tested was that there is no overall difference between any of the fibrinolytic agents available to the majority of patients who are suitable for peripheral arterial thrombolysis.

 
Secondary objective

To assess the complication rates and determine whether complication rates are higher with certain fibrinolytic agents.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Trials were included if participants had been randomly allocated to receive peripheral arterial thrombolysis using a fibrinolytic agent that was compared with another fibrinolytic agent.

 

Types of participants

Participants were patients requiring peripheral arterial thrombolysis in an attempt to achieve patency following a thrombo-embolic occlusion of either a native peripheral artery or a thrombosed lower limb graft. Dialysis grafts and fistulae were excluded. Participants were included irrespective of diabetic status, use of aspirin or anticoagulation post thrombolysis, or use of concurrent heparin.

 

Types of interventions

All types of thrombolytic interventions, including low and high dose regimens, and all commercially available agents were considered. The focus of this review was the randomised comparison of different agents irrespective of dose and duration. It was the choice of agent and not the subsequent intervention that determined inclusion into the review.

 

Types of outcome measures

The following outcomes were measured:

  • vessel patency;
  • time to lysis;
  • limb salvage;
  • amputation;
  • death;
  • complications, specifically risk of major haemorrhage and stroke.

 

Search methods for identification of studies

 

Electronic searches

For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched March 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 3, part of The Cochrane Library, (www.thecochranelibrary.com). See Appendix 1 for details of the search strategy used to search CENTRAL. The Specialised Register is maintained by the TSC and is constructed from weekly electronic searches of MEDLINE, EMBASE, CINAHL, AMED, and through handsearching relevant journals. The full list of the databases, journals and conference proceedings which have been searched, as well as the search strategies used are described in the Specialised Register section of the Cochrane Peripheral Vascular Diseases Group module in The Cochrane Library (www.thecochranelibrary.com).

 

Searching other resources

For the original review the authors reviewed reference lists of papers found from the searches. Proceedings from the British Vascular Surgical Society, European Vascular Surgical Society, North American Society of Vascular Surgery, Society of Cardiovascular and Interventional Radiology of North America and Cardiovascular and Interventional Radiology Society of Europe meetings were also scanned for relevant trials. All major pharmaceutical firms were asked about unpublished trials that fitted the criteria described above. There were no restrictions on language.

 

Data collection and analysis

 

Selection of studies

The selection of trials for inclusion in this review was carried out independently by two of the authors. One author (IR) identified all possible trials and sent these to the second author (DCB) for consideration. Discrepancies were resolved by discussion. The criteria for selection of trials was as specified in the above section (Criteria for considering studies for this review). Eligible studies were assessed using the following criteria: randomisation technique, allocation concealment, whether the trial was double blinded and description of withdrawals and dropouts from the study. In the absence of consensus over the inclusion of a particular trial, the opinion of a third author (DK) was sought.

 

Data extraction and management

The following data were extracted from the available literature.

  1. Participants: age, sex distribution.
  2. Severity of ischaemia: Ankle Brachial Pressure Indices (ABPI), the European Consensus definition of critical ischaemia (Anonymous 1991), Fontaine classification (Fontaine 1954) and Ad Hoc Committee Recommendations (Anonymous 1986).
  3. Outcome measures: limb salvage, vessel or graft patency, time to lysis, amputation, death and complications.

 

Assessment of risk of bias in included studies

An assessment of the risk of bias in included studies was undertaken following the recommendations described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions 5.0.1 (Higgins 2009). This comprises a description and a judgement for each domain in a risk of bias table. Each entry addresses a specific feature of the study:

  • adequate sequence generation;
  • allocation concealment;
  • blinding;
  • incomplete outcome data addressed;
  • free of selective reporting;
  • free of other bias.

The judgement for each entry involves answering a question. Answering 'Yes' indicates low risk of bias, 'No' indicates high risk of bias, and 'Unclear' indicates either lack of information or uncertainty over the potential for bias.

 

Measures of treatment effect

For dichotomous data, odds ratios (OR) were calculated with 95% confidence intervals (CI). Individual patient data from different trials were not combined.

 

Sensitivity analysis

Sensitivity analysis was not carried out as insufficient trials were identified.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Index terms
 

Description of studies

See Characteristics of included studies, Characteristics of excluded studies and Characteristics of ongoing studies tables.

 

Results of the search

See Figure 1.

 FigureFigure 1. Study flow diagram.

 

Included studies

No additional studies were included in this update.

Five randomised controlled studies with a total of 687 patients fulfilled the inclusion criteria for consideration in this review (Berridge 1991; Mahler 2001; Meyerovitz 1990; Ouriel 1999; Schweizer 1996).

The study by Berridge et al (Berridge 1991) compared intravenous rt-PA, intra-arterial rt-PA and intra-arterial streptokinase in a total of 60 patients. Patients were randomised into three groups of 20 patients receiving either intra-arterial rt-PA, intra-arterial streptokinase or intravenous rt-PA. It was the only trial comparing intravenous rt-PA and intra-arterial streptokinase. All patients had critical limb ischaemia of less than 30 days duration.

Meyerovitz 1990 described 32 patients randomised to receive either rt-PA or urokinase infusion. The clinical status of the patients was not disclosed and the majority of patients (29 out of 32) had occlusion of an infrainguinal bypass graft.

Schweizer 1996 described 120 patients randomised into two groups of 60 patients to receive either intra-arterial urokinase or intra-arterial rt-PA. Forty-nine per cent of patients within this study had Fontaine IIb classification limb ischaemia (claudication at less than 200 m) and the average length of occlusion was 6.5 cm.

Mahler 2001 reported a trial of 234 patients randomised to receive rt-PA or urokinase either via a microporous balloon catheter or an end hole catheter. The majority of patients had native arterial occlusion with Fontaine stage II ischaemia (intermittent claudication).

The study by Ouriel (Ouriel 1999) reported the results of a phase II trial of 241 patients randomised to compare pro-urokinase 2 mg/hr, 4 mg/hr or 8 mg/hr with urokinase 4000 IU/min for four hours then 2000 IU/min thereafter.

There was considerable heterogeneity in the clinical status of the patient groups and in lesion characteristics between these studies. Meyerovitz 1990 did not define clinical status, Fontaine classification or ABPI for the study population; who had 44 cm length occlusions on average. Berridge 1991 included only patients with critical limb ischaemia, with an average occlusion length of 15 cm. The larger patient group of Schweizer 1996 included 49% of patients with Fontaine IIb claudication (walking distance of less than 200 m) and shorter occlusion lengths, mean 6.5 cm.

 

Excluded studies

For this update one additional study was excluded (Han 2010), making a total of eighteen excluded studies. The reasons for exclusion are documented in the Characteristics of excluded studies table.

 

Risk of bias in included studies

See Figure 2 and Figure 3 for a graphical summary of methodological quality for the included studies, based on the risk of bias domains.

 FigureFigure 2. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
 FigureFigure 3. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

 

Allocation

Five trials (Berridge 1991; Mahler 2001; Meyerovitz 1990; Ouriel 1999; Schweizer 1996) satisfied the inclusion criteria for adequate randomisation. Allocation concealment using sequential opaque envelopes was reported in the Meyerovitz 1990 trial.

 

Blinding

Neither patients nor observers were blinded to assignment status in the studies, with the exception of the study by Ouriel 1999. Differences in the volumes administered may have made this difficult. In the Ouriel 1999 study, the treatment volumes were kept the same for the different regimes.

 

Incomplete outcome data

The study by (Meyerovitz 1990) reported by intention to treat, with exclusions clearly identified and follow up available to 30 days.

Berridge (Berridge 1991) clearly described excluded patients but these were not included in the final analysis. Follow up to three months was available.

Schweizer (Schweizer 1996) appeared to have reported by intention to treat but exclusions or interruptions to therapy, if they occurred, were not clearly documented. Follow up was available to six months.

Ouriel (Ouriel 1999) clearly described treated patients but those not completing in their allocated group were excluded from the final analysis. Follow up was available to 30 days.

Mahler (Mahler 2001) recorded a total for patient withdrawals at six months but did not detail reasons for withdrawal. These patients did not appear to have been included in the final analysis.

 

Effects of interventions

The clinical heterogeneity and small patient numbers in all five studies limited their power and their likelihood of achieving a statistically significant result. The most useful method of assessing efficacy is by comparison of the most important outcome measures, which are vessel patency, time to lysis, limb salvage, amputation, death and minor and major complications. The study by Berridge (Berridge 1991) included a comparison of intravenous rt-PA and intra-arterial streptokinase and rt-PA.

 
Intravenous rt-PA versus intra-arterial streptokinase

(Berridge 1991)

 
Primary outcomes

a) Vessel patency: assessed angiographically and graded into the three categories of complete lysis, partial lysis and failure. Intravenous rt-PA was associated with complete or partial lysis in nine of 20 patients compared with 16 of 20 patients in the intra-arterial streptokinase group (OR 4.89, 95% CI 1.20 to 19.94).

b) Limb salvage: asymptomatic limb salvage rate was reported at 30 days and 3 months. The intravenous rt-PA group achieved asymptomatic limb salvage in nine of 20 patients compared with 12 of 20 patients in the intra-arterial streptokinase group (OR 1.83, 95% CI 0.52 to 6.43).

c) Amputation: the amputation rate was reported at 30 days. No amputation occurred within 30 days in the intravenous rt-PA group. However, it should be noted that five patients within the intravenous rt-PA group had ongoing critical limb ischaemia at 30 days and three additional interventions had occurred including two vascular reconstructions and one intra-arterial thrombolysis. In the intra-arterial streptokinase group seven of 20 patients underwent amputation.

d) Death: there was no significant difference in death rates between the groups at 30 days or at three months (OR 0.30, 95% CI 0.03 to 3.15).

 
Secondary outcomes

a) Major haemorrhagic complications occurred equally in the intra-arterial streptokinase and intravenous rt-PA groups (three out of 20 patients in each group). One patient in the intravenous rt-PA group developed a cerebral haemorrhage.

b) Minor haemorrhagic complications (bleeding without hypotension or requirement for blood transfusion) occurred more frequently in the intravenous rt-PA group (nine patients) compared with the intra-arterial streptokinase group (three patients).

 
Intra-arterial streptokinase versus intra-arterial rt-PA

(Berridge 1991)

 
Primary outcomes

a) Vessel patency: assessed angiographically and graded into the three categories of complete lysis, partial lysis and failure. There was a statistically significant difference between vessel patency in the intra-arterial rt-PA (20 of 20 patients) compared with intra-arterial streptokinase (16 of 20 patients) groups (P < 0.04).

b) Limb salvage: asymptomatic limb salvage rate was reported at 30 days and 3 months. The best rate of asymptomatic limb salvage was achieved with intra-arterial rt-PA (16 out of 20 patients). Intra-arterial streptokinase achieved limb salvage in 12 of 20 patients.

c) Amputation: the amputation rate at 30 days was lower with intra-arterial rt-PA than with intra-arterial streptokinase (P < 0.05, Mann-Whitney U test).

d) Death: there was no significant difference in death rates between the groups at 30 days or at three months.

 
Secondary outcomes

a) Major haemorrhagic complications occurred in three of 20 patients in the intra-arterial streptokinase group. No major complications occurred in the intra-arterial rt-PA group.

b) Minor haemorrhagic complications (bleeding without hypotension or requirement for blood transfusion) occurred more frequently with intra-arterial streptokinase (three patients) than with intra-arterial rt-PA (no patients).

 
Intra-arterial urokinase versus intra-arterial rt-PA

(Mahler 2001; Meyerovitz 1990; Schweizer 1996)

 
Primary outcomes

a) Vessel patency: Meyerovitz 1990 assessed vessel patency at 4, 8 or 16 and 24 hours after the start of treatment. Angiograms were assessed by a consensus panel blinded to treatment assignation who looked for the primary endpoint of 95% or greater clot lysis. There was no statistically significant difference between urokinase and rt-PA at 24 hours. However, rt-PA was significantly more rapid at achieving lysis at 8 hours (P = 0.04).

The study of Schweizer et al (Schweizer 1996) used angiography to assess vessel patency during initial lysis treatment at non-specified time periods and by colour Doppler sonography at initial completion of lysis and at six months follow up. Thrombolysis using rt-PA was associated with statistically better vessel patency, particularly in the popliteal and calf arteries (P < 0.05), both immediately after lysis and at six months follow up. Duration of treatment was shorter with rt-PA than urokinase (mean 2 hrs versus 24 hrs); however, statistical values were not recorded.

Mahler 2001 assessed vessel patency at unspecified time periods during thrombolysis and by ABPI and 'oscillograms' at six months follow up. There was no statistically significant difference between rt-PA and urokinase either immediately after lysis or at six months follow up.

b) Limb salvage: the paper by Mahler (Mahler 2001) did not directly record the limb salvage rate though there was a significant difference in the major amputation rate between rt-PA and urokinase. No significant difference in limb salvage for rt-PA or urokinase was seen in the studies by Schweizer 1996 (OR 0.47, 95% CI 0.04 to 5.36) and Meyerovitz 1990 (OR 0.62, 95% CI 0.09 to 4.32).

c) Amputation: recorded at 30 days by Meyerovitz 1990 and at six months follow up in the studies of Schweizer 1996 and Mahler 2001.There was no statistically significant difference between the two groups in either of the trials by Meyerovitz 1990 (OR 1.62, 95% CI 0.23 to 11.26) and Schweizer 1996 (OR 2.13, 95% CI 0.19 to 24.20). Mahler 2001 demonstrated a statistically significant increase in risk of major amputation in the rt-PA group compared with the urokinase group (OR 0.29, 95% CI 0.08 to 1.06).

d) Death: there was no statistically significant difference between rt-PA and urokinase in any of the three trials.

 
Secondary outcomes

a) Major complications: no significant difference between groups was evident. In the trial of Meyerovitz 1990 major haemorrhagic complications, defined as bleeding requiring surgery, transfusion of two or more units of blood or causing interruption of fibrinolytic infusion, occurred in five patients in the rt-PA group and three patients in the urokinase group (P = 0.39). Schweizer 1996 described one case of severe gastrointestinal haemorrhage consistent with a major complication. Mahler 2001 did not demonstrate a significant difference in bleeding complications between rt-PA and urokinase. There was no statistically significant difference in risk of cerebral haemorrhage with any of the agents in these trials.

b) Minor complications: no significant difference between groups was found. Meyerovitz 1990 described two minor bleeding episodes in the rt-PA group but none in the urokinase group. Schweizer 1996 described five patients (8%) with groin haematomas in the urokinase group compared with nine (15%) in the rt-PA group. There was no statistically significant difference between the rt-PA and urokinase groups in the trial by Mahler 2001 (OR 0.75, 95% CI 0.12 to 4.55).

 
Intra-arterial pro-urokinase versus intra-arterial urokinase

(Ouriel 1999)
This study was designed as a phase II randomised, double blind study with a primary endpoint of complete lysis (> 95%) of the occluding thrombus. The trial was designed to assess the dose response relationship for intra-arterial pro-urokinase (r-ProUK) and compared 2 mg/hr, 4 mg/hr and 8 mg/hr pro-urokinase (r-ProUK) with intra-arterial urokinase infused at 4000 IU/min for four hours and then 2000 IU/min thereafter. Secondary endpoints were recorded including death, major amputation and bleeding complications.

 
Primary outcomes

a) Vessel patency: this was assessed using angiography at eight and 24 hours and recorded using the TIMI classification (Thrombolysis in Myocardial Infarction) of Grade 0 - no lysis; grade 1- penetration but no perfusion; grade 2 - lysis to peripheral bed but slow flow; grade 3 - lysed and normal flow. There was no statistically significant difference in recanalization, defined as TIMI grade 2 or 3, at eight hours. The primary endpoint (complete lysis) increased from 39.3% in the 2 mg r-ProUK group to 56% in the 8 mg/hr r-ProUK group; 49.1% of patients in the urokinase group achieved complete lysis at eight hours.

b) Limb salvage: there was no statistically significant difference between any of the r-ProUK groups and urokinase.

c) Amputation: there was no statistically significant difference between any of the r-ProUK groups and urokinase.

d) Death: at 30 days the risk of mortality was 0% in the 2 mg/hr r-ProUK group versus 6.9% in the urokinase group. This was not statistically significant.

 
Secondary outcomes

a) Major haemorrhage: there was no statistically significant difference between any of the r-ProUK treatment groups and urokinase. No patient in any treatment group developed a cerebral haemorrhage.

b) Minor haemorrhage: minor bleeding complications did appear to follow a dose response curve in the r-ProUK group; however, there was no statistically significant difference when compared with urokinase (8 mg/hr r-ProUK 73.1% compared with urokinase 58.3%; P = 0.116).

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Index terms
 

Summary of main results

The available randomised trials contain different inclusion criteria, different outcome measures and relatively small numbers, which makes meaningful comparison very difficult.

Only one study looked at the use of intravenous rt-PA (Berridge 1991). This treatment was statistically significantly poorer in terms of 30 day and three month asymptomatic limb salvage rates and carried a significantly higher risk of haemorrhagic complications than intra-arterial rt-PA or intra-arterial streptokinase. In the same study, intra-arterial rt-PA offered significantly greater initially successful lysis (P < 0.04) and a significantly lower amputation rate than intra-arterial streptokinase. At 30 days, intra-arterial rt-PA gave a 20% increase in limb salvage over streptokinase, although this was not statistically significant.

Three studies compared intra-arterial urokinase to intra-arterial rt-PA. The study of Meyerovitz 1990 reported that intra-arterial rt-PA tended to cause more rapid initial lysis but clinical outcomes of limb loss, death and amputation were similar in both groups. Schweizer 1996 also demonstrated a significant reduction in treatment duration with intra-arterial rt-PA. Schweizer 1996 found that the initial recanalization rates were greater with intra-arterial rt-PA (P < 0.05) and this difference was sustained at six months. The study by Mahler 2001 was complicated by the use of two different techniques, end hole catheter versus microporous balloon infusion, in addition to urokinase and rt-PA. In the group treated by end hole catheter infusion the authors quote that rt-PA appeared to work more rapidly than urokinase, however it is difficult to extract the data from the paper that support this statement. The rates of limb loss or partial amputation were not significantly different between the groups.

A wide range of clinical presentations is seen within the trials reviewed, extending from patients with intermittent claudication to critical limb ischaemia; for example the study of Schweizer 1996 included a significant proportion of patients with claudication. Thrombolysis carries with it a small risk of bleeding complications including cerebral haemorrhage. Currently, in the United Kingdom, the risk to benefit ratio of thrombolysis means that fibrinolytic agents are not frequently employed for patients with claudication. It is questionable how representative the results, for example of Schweizer 1996, are for a population of patients with critical limb ischaemia.

The incidence of haemorrhagic complications with rt-PA varies significantly between the studies and this almost certainly reflects the very different fibrinolytic regimes employed. Berridge 1991 had the most conservative rt-PA regime (intra-arterial rt-PA 0.5 mg/hr) and found a lower haemorrhagic complication rate with intra-arterial rt-PA than with either intra-arterial streptokinase or intravenous rt-PA. Notably there was no significant difference in the duration of therapy between rt-PA or streptokinase. Meyerovitz 1990 used a 10 mg intrathrombic bolus followed by an infusion of 5 mg/hr. Major and minor haemorrhagic complications were more prevalent in the rt-PA group, however the difference was not statistically significant. Initial lysis was faster with rt-PA but this was not sustained at 24 hours. Schweizer 1996 used an intrathrombic 5 mg bolus with 5 mg/hr infusion and found no major haemorrhagic complications, however 15% of rt-PA patients had large groin haematomas compared with 8% in the urokinase group. Notably, this study incorporated a post-thrombolysis anticoagulation regime with heparin (20,000 IU/24 hrs for five days).

In terms of more novel fibrinolytic agents, limited information from phase II and phase III trials are available. Only one study described a comparison between intra-arterial urokinase and intra-arterial pro-urokinase (Ouriel 1999). Pro-urokinase has improved fibrin specificity and may therefore reduce the risk of bleeding complications related to thrombolysis. This trial was a phase II study designed to determine the optimum dose regimen for intra-arterial pro-urokinase and contained several different dose regimens for pro-urokinase versus a standard dose regimen for urokinase. A dose response curve for pro-urokinase was defined but there was no statistically significant difference between the highest dose of intra-arterial prourokinase and intra-arterial urokinase in terms of vessel patency, amputation rate, deaths or complication rate.

Results from the phase II and phase III trials with alfimperase have now been published and include safety and efficacy data for alfimperase and surgery free survival to 30 days against placebo (Han 2010). There was no significant difference on 30 day freedom from open vascular surgery between intrathrombus placebo and intrathrombus alfimperase. These trials have not been included in this review as they do not compare thrombolytic agents as described in the selection of types of studies. However, It should be noted that a significant improvement was demonstrated in the placebo group, possibly due to a mechanical effect of thrombolysis, and future studies may now need to consider a placebo control arm in any study design.

A number of randomised trials have compared the use of adjunctive agents such as glycoprotein IIb/IIIa receptor inhibitors with existing thrombolytic agents. Duda (Duda 2001) compared urokinase with and without abciximab and in a later trial Tepe (Tepe 2006) compared urokinase with abciximab against rt-PA with abxicimab. These trials have not been considered to represent a comparison of thrombolytic agents and are considered within a separate review examining infusion techniques (Kessel 2004).

 

Overall completeness and applicability of evidence

Overall, the evidence from these studies is very limited. The analysis suggests that intra-arterial rt-PA may be more effective than intra-arterial streptokinase or intravenous rt-PA but this is based on small numbers of studies. There is no evidence that intra-arterial rt-PA is more effective than intra-arterial urokinase in patients with critical limb ischaemia. Initial lysis may be more rapid with rt-PA depending on the regime. The incidence of haemorrhagic complications is not statistically significantly greater with intra-arterial rt-PA than with other equipotent regimes. The available evidence is insufficient to show any benefit in reduction of bleeding complications from the use of pro-urokinase.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Index terms

 

Implications for practice

The evidence is limited and consists of relatively small studies but suggests that intra-arterial rt-PA and intra-arterial urokinase may be equally effective in the treatment of critical limb ischaemia. There is less evidence in favour of intra-arterial streptokinase compared with intra-arterial rt-PA. Intravenous rt-PA appeared to be less effective than the alternative fibrinolytic agents. Complications are related to the individual fibrinolytic regime. Haemorrhagic complications tend to be more prevalent with high dose regimes of intra-arterial rt-PA and are significantly more prevalent with intravenous rt-PA. Overall, the level of evidence is such that it is not possible to draw reliable conclusions.

 
Implications for research

Future randomised trials should use accepted reporting standards and inclusion criteria. Multicentre trials will be required to definitively demonstrate any difference between rt-PA and urokinase and should include sufficient numbers to allow for clinical and lesion heterogeneity.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Index terms

We would like to thank the Cochrane Peripheral Vascular Disease Group for their assistance with this review and the Cochrane Consumer Network for providing a plain language summary.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Index terms
Download statistical data

 
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]

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Index terms
 

Appendix 1. CENTRAL search strategy


#1MeSH descriptor: [Thrombolytic Therapy] explode all trees1556

#2MeSH descriptor: [Fibrinolytic Agents] this term only and with qualifiers: [Administration & dosage - AD]596

#3MeSH descriptor: [Plasminogen Activators] explode all trees and with qualifiers: [Administration & dosage - AD]662

#4urokinase or streptokinase or streptase or tenecteplase:ti,ab,kw (Word variations have been searched)1885

#5reteplase or alteplase:ti,ab,kw (Word variations have been searched)413

#6anistreplase or prourokinase or retavase or rapilysin:ti,ab,kw (Word variations have been searched)206

#7t-PA or tPA:ti,ab,kw (Word variations have been searched)954

#8r-PA or rPA:ti,ab,kw (Word variations have been searched)53

#9lysis:ti,ab,kw (Word variations have been searched)691

#10plasminogen near/2 activator3004

#11clot near/3 (bust* or break* or remov*):ti,ab,kw (Word variations have been searched)54

#12thrombolysis2457

#13#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #126691

#14MeSH descriptor: [Arteriosclerosis] this term only893

#15MeSH descriptor: [Arteriolosclerosis] this term only0

#16MeSH descriptor: [Arteriosclerosis Obliterans] this term only71

#17MeSH descriptor: [Atherosclerosis] this term only382

#18MeSH descriptor: [Arterial Occlusive Diseases] this term only755

#19MeSH descriptor: [Intermittent Claudication] this term only711

#20MeSH descriptor: [Ischemia] this term only753

#21MeSH descriptor: [Peripheral Vascular Diseases] explode all trees2150

#22MeSH descriptor: [Vascular Diseases] this term only381

#23MeSH descriptor: [Leg] explode all trees and with qualifiers: [Blood supply - BS]1075

#24MeSH descriptor: [Femoral Artery] explode all trees720

#25MeSH descriptor: [Popliteal Artery] explode all trees250

#26MeSH descriptor: [Iliac Artery] explode all trees151

#27MeSH descriptor: [Tibial Arteries] explode all trees29

#28(atherosclero* or arteriosclero* or PVD or PAOD or PAD)17195

#29(arter*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*)4872

#30(vascular) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*)1378

#31(vein*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*)713

#32(veno*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*)976

#33(peripher*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*)1358

#34(peripheral near/3 (dis* or thrombo*))3349

#35arteriopathic10

#36(claudic* or hinken*)1436

#37(isch* or CLI)16827

#38dysvascular*14

#39leg near/4 (obstruct* or occlus* or steno* or block* or obliter*)176

#40limb near/4 (obstruct* or occlus* or steno* or block* or obliter*)228

#41(lower near/3 extrem*) near/4 (obstruct* or occlus* or steno* or block* or obliter*)137

#42(aort* or iliac or femoral or popliteal or femoro* or fempop* or crural) near/3 (obstruct* or occlus*)326

#43((bypass or graft) near/3 (*occlus* or steno* or restenos* or obstuct* or lesio* or block* or obliter*))887

#44#14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #4339771

#45#13 and #44 in Trials1996



 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Index terms

Last assessed as up-to-date: 21 March 2013.


DateEventDescription

10 October 2013New citation required but conclusions have not changedSearches re-run. No new included studies and one additional excluded study were identified. No change to conclusions. Minor edits made.

10 October 2013New search has been performedSearches re-run. No new included studies and one additional excluded study were identified.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Index terms

Iain Robertson selected the trials, wrote the text of the review, interpreted and extracted trial data, and worked on the review manuscript.

David C Berridge selected trials, interpreted and extracted trial data, and reviewed the manuscript.

David Kessel interpreted study data and reviewed the manuscript.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Index terms

David Berridge is an author of the Berridge 1991 study which is included in the review.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.
    The PVD Group editorial base is supported by the Chief Scientist Office.

 

Notes

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Index terms

This is the third of three reviews concerning surgical techniques for thrombolysis.

The first review is 'Surgery versus thrombolysis for initial management of acute limb ischaemia' (Berridge 2013). The second review is 'Infusion techniques for peripheral arterial thrombolysis' (Kessel 2004).

 

Index terms

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Notes
  16. Index terms

Medical Subject Headings (MeSH)

Arterial Occlusive Diseases [*drug therapy]; Fibrinolytic Agents [adverse effects; *therapeutic use]; Peripheral Vascular Diseases [*drug therapy]; Randomized Controlled Trials as Topic; Recombinant Proteins [adverse effects; therapeutic use]; Streptokinase [adverse effects; therapeutic use]; Thrombolytic Therapy [adverse effects; *methods]; Thrombosis [*drug therapy]; Tissue Plasminogen Activator [adverse effects; therapeutic use]; Urokinase-Type Plasminogen Activator [adverse effects; therapeutic use]

MeSH check words

Humans

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé scientifique
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Notes
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
  21. References to other published versions of this review
Berridge 1991 {published data only}
  • Berridge DC, Gregson RHS, Hopkinson BR, Makin GS. Randomized trial of intra-arterial recombinant tissue plasminogen activator, intravenous recombinant tissue plasminogen activator and intra-arterial streptokinase in peripheral arterial thrombolysis. British Journal of Surgery 1991;78:988-95.
Mahler 2001 {published data only}
  • Mahler F, Schneider E, Hess H, Steering Committee, Study on Local Thrombolysis. Recombinant tissue plasminogen activator versus urokinase for local thrombolysis of femoropopliteal occlusions: A prospective, randomized multicenter trial. Journal of Endovascular Therapy 2001;8(6):638-47.
Meyerovitz 1990 {published data only}
  • Meyerovitz MF, Goldhaber SZ, Reagan K, Polak JF, Kandarpa K, Grassi C, et al. Recombinant tissue-type plasminogen versus urokinase in peripheral arterial and graft occlusions: A randomized trial. Radiology 1990;175:75-8.
Ouriel 1999 {published data only}
  • Ouriel K, Kandarpa K, Krishna MD, Scheurr D, Hultquist M, Hodkinson G, et al. Prourokinase vs urokinase for recanalization of peripheral occlusions, safety and efficacy: The PURPOSE trial. Journal of Vascular and Interventional Radiology 1999;10(8):1083-91.
Schweizer 1996 {published data only}
  • Schweizer J, Altmann E, Stoblein F, Florek HJ, Kaulen R. Comparision of tissue plasminogen activator and urokinase in the local infiltration thrombolysis of peripheral arterial occlusions. European Journal of Radiology 1996;22:129-32.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé scientifique
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Notes
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
  21. References to other published versions of this review
Braithwaite 1997 {published data only}
  • Braithwaite BD, Buckenham TM, Galland RB, Heather BP, Earnshaw JJ. Prospective randomized trial of high-dose bolus versus low-dose tissue plasminogen activator infusion in the management of acute limb ischaemia. British Journal of Surgery 1997;84(5):646-50.
  • Braithwaite BD, Virgo H, Earnshaw JJ. The systematic effects of high dose bolus and low dose intra-arterial thrombolysis with tissue plasminogen activator (t-PA) for acute limb ischaemia. Thrombosis and Haemostasis. 1997; Vol. 503 Abstract No PS-2058, issue Supplement June.
Cina 1999 {published data only}
  • Cina CS, Goh RH, Chan J, Kenny B, Evans G, Rawlinson J, et al. Intraarterial catheter-directed thrombolysis: urokinase versus tissue plasminogen activator. Annals of Vascular Surgery 1999;13(6):571-5.
Dawson 1991 {published data only}
Dawson 1991a {published data only}
  • Dawson KJ, Hehir D, Hamilton G. Low dose intra-arterial streptokinase compared with tissue plasminogen activator in acute lower limb ischaemia. Irish Journal of Medical Science 1991;160:216-7.
Didier 1995 {published data only}
  • Didier D, Meyerovitz MF, Vogel JJ, Soulier L, Bounameaux H. Thrombolysis versus mechanical recanalisation of chronic peripheral arterial occlusions. Randomized study. Schweizerische Medizinische Wochenschrift 1995;125:11.
Dube 1996 {published data only}
  • Dube M, Soulez G, Therasse E, Cartier P, Blair JF, Roy P, et al. Comparison of streptokinase and urokinase in local thrombolysis of peripheral arterial occlusions for lower limb salvage. Journal of Vascular and Interventional Radiology 1996;7(4):587-93.
Duda 2001 {published data only}
  • Duda S, Tepe G, Luz O, Ouriel K, Dietz K, Hahn U, et al. Peripheral arterial occlusion: treatment with abxcimab plus urokinase versus urokinase alone - a randomised pilot trial (the PROMPT trial). Radiology 2001;221:689-96.
Gryglewski 1995 {published data only}
  • Gryglewski RJ, Szczeklik A, Korbut R, Swies J, Musial J, Krzanowski M, et al. The mechanism of anti-thrombotic, thrombolytic and fibrinolytic actions of camonagrel--a new thromboxane synthase inhibitor. Wiener Klinische Wochenschrift 1995;107:283-9.
Han 2010 {published data only}
  • Han SM, Weaver FA, Comerota AJ, Perler BA, Joing M. Efficacy and safety of alfimeprase in patients with acute peripheral arterial occlusion (PAO). Journal of Vascular Surgery 2010;51(3):600-9.
Hess 1996 {published data only}
  • Hess H, Mietaschk A, von Bilderling P, Neller P. Peripheral arterial occlusions: local low-dose thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA). European Journal of Vascular and Endovascular Surgery 1996;12(1):97-104.
Hiatt 2002 {published data only}
  • Hiatt WR. Abciximab added to urokinase increased amputation-free survival in peripheral arterial occlusion of the legs. American College of Physicians Journal Club 2002;137(1):12.
Reichle 1976 {published data only}
Sarif 2005 {published data only}
  • Sarif J, Lindhoff-Last E, Bauersachs R. Rebound after discontinuation of long-term oral anticoagulation (OAC): Effects of a 4 week course of LMWH on VTE recurrences. Journal of Thrombosis and Haemostasis. 2005; Vol. 3, issue 1:Abstract no: P1024.
Schulman 1996 {published data only}
STILE 1994 {published data only}
Tepe 2006 {published data only}
  • Tepe G, Hopfenzitz C, Dietz K, Wiskirchen J, Heller S, Ouriel K, et al. Peripheral Arteries: Treatment with antibodies of platelet receptors and reteplase for thrombolysis-APART trial. Radiology 2006;239(3):892-900.
Vanderschueren 1995 {published data only}
  • Vanderschueren S, Stockx L, Wilms G, Lacroix H, Verhaege R, Vermuylen J, et al. Thrombolytic therapy of peripheral arterial occlusion with recombinant staphylokinase. Circulation 1995;92(8):2050-7.
Wen 2005 {published data only}
  • Wen Y, Rong C, Yu W, Qian Z, Shu-rong L, Ning L, et al. Effect of urokinase injected by volumetric infusion pump on rest pain, intermittent limp and walking distance in aged patients with arteriosclerosis obliterans of the lower limbs. Zhongguo Linchuang Kangfu 2005;9(30):232-3.

Additional references

  1. Top of page
  2. AbstractRésumé scientifique
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Notes
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
  21. References to other published versions of this review
Anonymous 1986
  • Ad Hoc Committee on Reporting Standards, Society for Vascular Surgery/North American Chapter International Society for Cardiovascular Surgery. Suggested standards for reports dealing with lower extremity ischaemia. Journal of Vascular Surgery 1986;4(1):80-94.
Anonymous 1991
  • Anonymous. Second European Consensus Document on chronic critical leg ischaemia. Circulation 1991;84 Suppl IV(4):1-26.
Berridge 2013
Fontaine 1954
  • Fontaine VR, Kim M, Kieny R. Die chirurgische Behandlung der peripheren Durchblutungsstorungen [Die chirurgische Behandlung der peripheren Durchblutungsstorungen]. Helvetica Chirurgica Acta 1954;5/6:499-533.
Higgins 2009
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009]. The Cochrane Collaboration, 2009. Available from www.cochrane-handbook.org.
Kessel 2004
  • Kessel DO, Berridge DC, Robertson I. Infusion techniques for peripheral arterial thrombolysis. Cochrane Database of Systematic Reviews 2004, Issue 1. [DOI: 10.1002/14651858.CD000985.pub2]