Cochrane Database of Systematic Reviews

Fibrinolytic agents for peripheral arterial occlusion (Review) Robertson I, Kessel DO, Berridge DC

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.

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Fibrinolytic agents for peripheral arterial occlusion (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Intra-arterial streptokinase versus intravenous rt-PA, Outcome 1 Vessel Patency immediately post lysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.2. Comparison 1 Intra-arterial streptokinase versus intravenous rt-PA, Outcome 2 Asymptomatic Limb salvage at 30 days. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.3. Comparison 1 Intra-arterial streptokinase versus intravenous rt-PA, Outcome 3 Amputation at 30 days. Analysis 1.4. Comparison 1 Intra-arterial streptokinase versus intravenous rt-PA, Outcome 4 Death. . . . . . . Analysis 1.5. Comparison 1 Intra-arterial streptokinase versus intravenous rt-PA, Outcome 5 Complications- major haemorrhage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.6. Comparison 1 Intra-arterial streptokinase versus intravenous rt-PA, Outcome 6 Complications- minor haemorrhage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.1. Comparison 2 Intra-arterial streptokinase versus intra-arterial rt-PA, Outcome 1 Vessel patency immediately post lysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.2. Comparison 2 Intra-arterial streptokinase versus intra-arterial rt-PA, Outcome 2 Asymptomatic Limb salvage at 30 days. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.3. Comparison 2 Intra-arterial streptokinase versus intra-arterial rt-PA, Outcome 3 Amputation at 30 days. Analysis 2.4. Comparison 2 Intra-arterial streptokinase versus intra-arterial rt-PA, Outcome 4 Death. . . . . . . Analysis 2.5. Comparison 2 Intra-arterial streptokinase versus intra-arterial rt-PA, Outcome 5 Complications- major haemorrhage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.6. Comparison 2 Intra-arterial streptokinase versus intra-arterial rt-PA, Outcome 6 Complications- minor haemorrhage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.1. Comparison 3 Intra-arterial urokinase versus intra-arterial rt-PA, Outcome 1 Vessel patency immediately post lysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.2. Comparison 3 Intra-arterial urokinase versus intra-arterial rt-PA, Outcome 2 Limb salvage. . . . . . Analysis 3.3. Comparison 3 Intra-arterial urokinase versus intra-arterial rt-PA, Outcome 3 Major amputation at 30 days-6 months. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.4. Comparison 3 Intra-arterial urokinase versus intra-arterial rt-PA, Outcome 4 Death. . . . . . . . Analysis 3.5. Comparison 3 Intra-arterial urokinase versus intra-arterial rt-PA, Outcome 5 Complications - major haemorrhage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.6. Comparison 3 Intra-arterial urokinase versus intra-arterial rt-PA, Outcome 6 Complications - minor haemorrhage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fibrinolytic agents for peripheral arterial occlusion (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Fibrinolytic agents for peripheral arterial occlusion (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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[Intervention Review]

Fibrinolytic agents for peripheral arterial occlusion Iain Robertson1 , David O Kessel2 , David C Berridge3 1 Department of Radiology, Gartnavel General Hospital, Glasgow, UK. 2 Department of Clinical Radiology, Leeds Teaching Hospitals Trust, Leeds, UK. 3 Leeds Vascular Institute, Leeds General Infirmary, Leeds, UK

Contact address: Iain Robertson, Department of Radiology, Gartnavel General Hospital, 1053 Great Western Road, Glasgow, G12 0XN, UK. [email protected]. [email protected]. Editorial group: Cochrane Vascular Group. Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 12, 2013. Review content assessed as up-to-date: 21 March 2013. Citation: 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. Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Peripheral arterial thrombolysis is used in the management of peripheral arterial ischaemia. Streptokinase was originally used but safety concerns led to a search for other agents. Urokinase and recombinant tissue plasminogen activator (rt-PA) have increasingly become established as first line agents for peripheral arterial thrombolysis. Potential advantages of these agents include improved safety, greater efficacy and a more rapid response. Recently drugs such as pro-urokinase, recombinant staphylokinase and alfimperase have been introduced. This is an update of a review first published in 2010. Objectives To determine which fibrinolytic agents are most effective in peripheral arterial ischaemia. Search methods For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched March 2013) and CENTRAL (2013, Issue 3) for randomised controlled trials (RCTs) comparing fibrinolytic agents to treat peripheral arterial ischaemia. Selection criteria RCTs comparing fibrinolytic agents to treat peripheral arterial occlusion. Data collection and analysis Data were analysed for the outcomes vessel patency, time to lysis, limb salvage, amputation, death, complications including major haemorrhage, stroke, and distal embolization. Main results Five RCTs involving a total of 687 participants with a range of clinical indications were included. No new studies were included in this update. In one three-pronged study, vessel patency was greater with intra-arterial recombinant tissue plasminogen activator (rtPA) than with intra-arterial streptokinase (P < 0.04) or intravenous rt-PA (P < 0.01). In participants with peripheral arterial occlusion there was no statistically significant difference in limb salvage at 30 days with either urokinase or rt-PA, though this may reflect the small numbers in the studies. Incidences of haemorrhagic complications varied with fibrinolytic regime but there was no statistically significant difference between intra-arterial urokinase and intra-arterial rt-PA. In the three-pronged study intravenous rt-PA and intraFibrinolytic agents for peripheral arterial occlusion (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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arterial streptokinase were associated with a significantly higher risk of haemorrhagic complications than with intra-arterial rt-PA (P < 0.05). Authors’ conclusions There is some evidence to suggest that intra-arterial rt-PA is more effective than intra-arterial streptokinase or intravenous rt-PA in improving vessel patency in people with peripheral arterial occlusion. There was no evidence that rt-PA was more effective than urokinase for patients with peripheral arterial occlusion and some evidence that initial lysis may be more rapid with rt-PA, depending on the regime. Incidences of haemorrhagic complications were not statistically significantly greater with rt-PA than with other regimes. However, all of the findings come from small studies and a general paucity of results means that it is not possible to draw clear conclusions.

PLAIN LANGUAGE SUMMARY Drugs to break down blood clots for people with sudden onset peripheral arterial occlusion Acute reduction in blood flow to a limb can be caused by a blood clot blocking an artery or a vascular graft. If not treated promptly this condition, known as peripheral arterial occlusion, can result in amputation or be life threatening. Infusion of clot-busting drugs can restore blood flow by dissolving the clot (thrombolysis). This review found some evidence from five randomized controlled trials, involving a total of 687 patients that suggested local infusion of a drug into the affected artery is more effective than infusion into a vein, and is also associated with a lower risk of unwanted bleeding. No particular drug was more effective in preventing limb loss or death than another. The drugs investigated were streptokinase, urokinase, recombinant tissue plasminogen activator and pro-urokinase. More research is needed to confirm these findings. All of the findings of this review came from small studies that involved people with peripheral arterial ischaemia of differing severity.

BACKGROUND 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.

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Description of the intervention

Types of studies

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.

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.

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

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.

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

Criteria for considering studies for this review

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).

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Searching other resources

Assessment of risk of bias in included studies

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.

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.

Data collection and analysis

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.

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.

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 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.

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.

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Figure 1. Study flow diagram.

Fibrinolytic agents for peripheral arterial occlusion (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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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.

Fibrinolytic agents for peripheral arterial occlusion (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Figure 2. Methodological quality summary: review authors’ judgements about each methodological quality item for each included study.

Fibrinolytic agents for peripheral arterial occlusion (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Figure 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.

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.

Blinding

Effects of interventions

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.

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. Intra-

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venous 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 rtPA 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 intraarterial 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). Intraarterial 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).

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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).

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

Summary of main results 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 (rProUK) 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 rProUK group; 49.1% of patients in the urokinase group achieved complete lysis at eight hours.

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 intraarterial 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

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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 intraarterial 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 intraarterial 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 intraarterial 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 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 defini-

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tively demonstrate any difference between rt-PA and urokinase and should include sufficient numbers to allow for clinical and lesion heterogeneity.

ACKNOWLEDGEMENTS 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.

REFERENCES

References to studies included in 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 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 KJ, Reddy K, Platts AD, Hamilton G. Results of a recently instituted programme of thrombolytic therapy in acute lower limb ischaemia. British Journal of Surgery 1991; 78(4):409–11. 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.

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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} Reichle FA, Rao NS, Chang KHY, et al. Fibrinolytic treatment of acute or subacute arterial thrombosis. Surgical Forum 1976;27:219–21. 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} Schulman S, Wiman B. The significance of hypofibrinolysis for the risk of recurrence of venous thromboembolism. Thrombosis and Haemostasis 1996;75:607–11. STILE 1994 {published data only} The STILE investigators. Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischaemia of the lower extremity. Annals of Surgery 1994; 220(3):251–68. 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 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 Berridge DC, Kessel D, Robertson I. Surgery versus thrombolysis for initial management of acute limb ischaemia. Cochrane Database of Systematic Reviews 2013, Issue 6. [DOI: 10.1002/14651858.CD002784.pub2] 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]

References to other published versions of this review Robertson 2010 Robertson I, Kessel DO, Berridge DC. Fibrinolytic agents for peripheral arterial occlusion. Cochrane Database of Systematic Reviews 2010, Issue 3. [DOI: 10.1002/ 14651858.CD001099.pub2] ∗ Indicates the major publication for the study

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CHARACTERISTICS OF STUDIES

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

Study design: RCT parallel group.

Participants

Country: 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 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

Outcomes

Primary: vessel patency, time to lysis, amputation, death. Secondary: complications including bleeding and cerebral haemorrhage

Notes

Techniques 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 Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

Randomised in blocks of 10.

Allocation concealment (selection bias)

Method not stated.

Unclear risk

Blinding (performance bias and detection High risk bias) All outcomes

Not blinded.

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Mahler 2001

(Continued)

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

55 patients lost to follow up but no information on statistical handling of missing data Exclusion post-randomisation: none recorded.

Selective reporting (reporting bias)

Low risk

All primary and secondary outcomes reported.

Other bias

Unclear risk

Supported by a grant from Boehringer Ingelheim who manufactured the Alteplase

Meyerovitz 1990 Methods

Study design: RCT.

Participants

Country: 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

Outcomes

Primary: 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

Notes

Lysis 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 Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk bias)

Randomised by means of consecutive numbers.

Allocation concealment (selection bias)

Sealed envelopes.

Unclear risk

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Meyerovitz 1990

(Continued)

Blinding (performance bias and detection High risk bias) All outcomes

Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

Exclusions post-randomisation: none recorded. No losses to follow up.

Selective reporting (reporting bias)

Low risk

All outcomes reported.

Other bias

Unclear risk

Supported in part by Genentech Inc (Activase manufacturer) and Abbott Laboratories (Abbokinase manufacturer)

Ouriel 1999 Methods

Phase II randomised, multicentre double blind study.

Participants

Country: 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.

Outcomes

Primary: vessel patency, time to lysis, dose of study drug, amputation, death Secondary: complications including bleeding.

Notes

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

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk bias)

Randomisation was stratified by type of occlusion; native artery or bypass graft

Allocation concealment (selection bias)

Method not stated.

Unclear risk

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Ouriel 1999

(Continued)

Blinding (performance bias and detection Low risk bias) All outcomes

Double blind.

Incomplete outcome data (attrition bias) All outcomes

Low risk

All 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 risk

All outcomes reported.

Other bias

Unclear risk

Some authors were affiliated to Abbott Laboratories manufacturers of Abbokinase

Schweizer 1996 Methods

Study design: RCT.

Participants

Country: 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.

Outcomes

Primary: amputation, Fontaine, ABPI, vessel patency. Secondary: death.

Notes

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

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk bias)

States randomised but method not given.

Allocation concealment (selection bias)

Not stated.

Unclear risk

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Schweizer 1996

(Continued)

Blinding (performance bias and detection High risk bias) All outcomes

Not blinded.

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

Exclusions post-randomisation: none recorded. Two patients lost to follow-up but no information on statistical handling of missing data

Selective reporting (reporting bias)

Low risk

All outcomes reported.

Other bias

Unclear risk

No declarations of interest stated, no information given regarding sponsorship

i.a. intra-arterial IU international units i.v. intravenous RCT randomised controlled trial rt-PA recombinant tissue plasminogen activator SK streptokinase UK urokinase

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Braithwaite 1997

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

Cina 1999

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

Dawson 1991

Non-randomised streptokinase vs rt-PA

Dawson 1991a

Non-randomised

Didier 1995

Comparison of angioplasty versus rt-PA and angioplasty

Dube 1996

Only partially randomised 10 of 40 patients; insufficient for analysis

Duda 2001

Not 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 1995

Not a comparison of thrombolytic agents

Han 2010

Paper 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

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(Continued)

Hess 1996

Non-comparative and non-randomised

Hiatt 2002

Not a comparison of agents

Reichle 1976

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

Sarif 2005

Not arterial thrombolysis

Schulman 1996

Venous thromboembolism

STILE 1994

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

Tepe 2006

Comparison 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 1995

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

Wen 2005

Comparison of urokinase and danshen root

rt-PA recombinant tissue plasminogen activator

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DATA AND ANALYSES

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

Outcome or subgroup title 1 Vessel Patency immediately post lysis 2 Asymptomatic Limb salvage at 30 days 3 Amputation at 30 days 4 Death 5 Complications- major haemorrhage 6 Complications- minor haemorrhage

No. of studies

No. of participants

Statistical method

Effect size

1

Odds Ratio (M-H, Fixed, 95% CI)

Totals not selected

1

Odds Ratio (M-H, Fixed, 95% CI)

Totals not selected

1 1 1

Odds Ratio (M-H, Fixed, 95% CI) Odds Ratio (M-H, Fixed, 95% CI) Odds Ratio (M-H, Fixed, 95% CI)

Totals not selected Totals not selected Totals not selected

1

Odds Ratio (M-H, Fixed, 95% CI)

Totals not selected

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

Outcome or subgroup title 1 Vessel patency immediately post lysis 2 Asymptomatic Limb salvage at 30 days 3 Amputation at 30 days 4 Death 5 Complications- major haemorrhage 6 Complications- minor haemorrhage

No. of studies

No. of participants

Statistical method

Effect size

1

Odds Ratio (M-H, Fixed, 95% CI)

Totals not selected

1

Odds Ratio (M-H, Fixed, 95% CI)

Totals not selected

1 1 1

Odds Ratio (M-H, Fixed, 95% CI) Odds Ratio (M-H, Fixed, 95% CI) Odds Ratio (M-H, Fixed, 95% CI)

Totals not selected Totals not selected Totals not selected

1

Odds Ratio (M-H, Fixed, 95% CI)

Totals not selected

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

Outcome or subgroup title 1 Vessel patency immediately post lysis 2 Limb salvage 3 Major amputation at 30 days-6 months

No. of studies

No. of participants

3 3 3

368

Statistical method

Effect size

Odds Ratio (M-H, Fixed, 95% CI)

Totals not selected

Odds Ratio (M-H, Fixed, 95% CI) Odds Ratio (M-H, Fixed, 95% CI)

1.68 [0.68, 4.15] Totals not selected

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4 Death 5 Complications - major haemorrhage 6 Complications - minor haemorrhage

3 3

368 298

Odds Ratio (M-H, Fixed, 95% CI) Odds Ratio (M-H, Fixed, 95% CI)

0.79 [0.24, 2.54] 0.68 [0.19, 2.40]

3

386

Odds Ratio (M-H, Fixed, 95% CI)

0.50 [0.20, 1.26]

Analysis 1.1. Comparison 1 Intra-arterial streptokinase versus intravenous rt-PA, Outcome 1 Vessel Patency immediately post lysis. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 1 Intra-arterial streptokinase versus intravenous rt-PA Outcome: 1 Vessel Patency immediately post lysis

Study or subgroup

Berridge 1991

i.a streptokinase

i.v. rt-PA

Odds Ratio

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

M-H,Fixed,95% CI

16/20

9/20

4.89 [ 1.20, 19.94 ]

0.01

0.1

1

Favours rt-PA

10

100

Favours i.a. strept.

Analysis 1.2. Comparison 1 Intra-arterial streptokinase versus intravenous rt-PA, Outcome 2 Asymptomatic Limb salvage at 30 days. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 1 Intra-arterial streptokinase versus intravenous rt-PA Outcome: 2 Asymptomatic Limb salvage at 30 days

Study or subgroup

Berridge 1991

i.a. streptokinase

i.v. rt-PA

Odds Ratio

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

M-H,Fixed,95% CI

12/20

9/20

1.83 [ 0.52, 6.43 ]

0.001 0.01 0.1 Favours i.v. rt-PA

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10 100 1000 Favours i.a. strept.

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Analysis 1.3. Comparison 1 Intra-arterial streptokinase versus intravenous rt-PA, Outcome 3 Amputation at 30 days. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 1 Intra-arterial streptokinase versus intravenous rt-PA Outcome: 3 Amputation at 30 days

Study or subgroup

Berridge 1991

i.a. streptokinase

i.v. rt-PA

Odds Ratio

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

M-H,Fixed,95% CI

7/20

0/20

22.78 [ 1.20, 432.58 ]

0.001 0.01 0.1

1

Favours i.a. strept.

10 100 1000 Favours i.v. rt-PA

Analysis 1.4. Comparison 1 Intra-arterial streptokinase versus intravenous rt-PA, Outcome 4 Death. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 1 Intra-arterial streptokinase versus intravenous rt-PA Outcome: 4 Death

Study or subgroup

Berridge 1991

i.a. streptokinase

i.v. rt-PA

Odds Ratio

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

M-H,Fixed,95% CI

1/20

3/20

0.30 [ 0.03, 3.15 ]

0.001 0.01 0.1 Favours i.a. strept.

Fibrinolytic agents for peripheral arterial occlusion (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Analysis 1.5. Comparison 1 Intra-arterial streptokinase versus intravenous rt-PA, Outcome 5 Complications- major haemorrhage. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 1 Intra-arterial streptokinase versus intravenous rt-PA Outcome: 5 Complications- major haemorrhage

Study or subgroup

Berridge 1991

i.a. streptokinase

i.v. rt-PA

Odds Ratio

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

M-H,Fixed,95% CI

3/20

3/20

1.00 [ 0.18, 5.67 ]

0.02

0.1

1

Favours i.a. strept.

10

50

Favours i.v. rt-PA

Analysis 1.6. Comparison 1 Intra-arterial streptokinase versus intravenous rt-PA, Outcome 6 Complications- minor haemorrhage. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 1 Intra-arterial streptokinase versus intravenous rt-PA Outcome: 6 Complications- minor haemorrhage

Study or subgroup

Berridge 1991

i.a. streptokinase

i.v. rt-PA

Odds Ratio

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

M-H,Fixed,95% CI

3/20

9/20

0.22 [ 0.05, 0.98 ]

0.01

0.1

Favours i.a. strept.

Fibrinolytic agents for peripheral arterial occlusion (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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10

100

Favours i.v. rt-PA

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Analysis 2.1. Comparison 2 Intra-arterial streptokinase versus intra-arterial rt-PA, Outcome 1 Vessel patency immediately post lysis. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 2 Intra-arterial streptokinase versus intra-arterial rt-PA Outcome: 1 Vessel patency immediately post lysis

Study or subgroup

Berridge 1991

i.a. streptokinase

i.a. rt-PA

Odds Ratio

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

M-H,Fixed,95% CI

16/20

20/20

0.09 [ 0.00, 1.78 ]

0.01

0.1

1

Favours i.a. rt-PA

10

100

Favours i.a.strept

Analysis 2.2. Comparison 2 Intra-arterial streptokinase versus intra-arterial rt-PA, Outcome 2 Asymptomatic Limb salvage at 30 days. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 2 Intra-arterial streptokinase versus intra-arterial rt-PA Outcome: 2 Asymptomatic Limb salvage at 30 days

Study or subgroup

Berridge 1991

i.a. streptokinase

i.a. rt-PA

Odds Ratio

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

M-H,Fixed,95% CI

12/20

16/20

0.38 [ 0.09, 1.54 ]

0.001 0.01 0.1 Favours i.a. rt-PA

Fibrinolytic agents for peripheral arterial occlusion (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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10 100 1000 Favours i.a. strept.

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Analysis 2.3. Comparison 2 Intra-arterial streptokinase versus intra-arterial rt-PA, Outcome 3 Amputation at 30 days. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 2 Intra-arterial streptokinase versus intra-arterial rt-PA Outcome: 3 Amputation at 30 days

Study or subgroup

Berridge 1991

i.a. streptokinase

i.a. rt-PA

Odds Ratio

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

M-H,Fixed,95% CI

7/20

1/20

10.23 [ 1.12, 93.34 ]

0.001 0.01 0.1

1

Favours i.a. strept.

10 100 1000 Favours i.a. rt-PA

Analysis 2.4. Comparison 2 Intra-arterial streptokinase versus intra-arterial rt-PA, Outcome 4 Death. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 2 Intra-arterial streptokinase versus intra-arterial rt-PA Outcome: 4 Death

Study or subgroup

Berridge 1991

i.a. streptokinase

i.a. rt-PA

Odds Ratio

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

M-H,Fixed,95% CI

2/20

4/20

0.44 [ 0.07, 2.76 ]

0.001 0.01 0.1 Favours i.a. strept.

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10 100 1000 Favours i.a. rt-PA

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Analysis 2.5. Comparison 2 Intra-arterial streptokinase versus intra-arterial rt-PA, Outcome 5 Complications- major haemorrhage. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 2 Intra-arterial streptokinase versus intra-arterial rt-PA Outcome: 5 Complications- major haemorrhage

Study or subgroup

Berridge 1991

i.a. streptokinase

i.a. rt-PA

Odds Ratio

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

M-H,Fixed,95% CI

3/20

0/20

8.20 [ 0.40, 169.90 ]

0.005

0.1

1

Favours i.a. strept

10

200

Favours i.a. rt-PA.

Analysis 2.6. Comparison 2 Intra-arterial streptokinase versus intra-arterial rt-PA, Outcome 6 Complications- minor haemorrhage. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 2 Intra-arterial streptokinase versus intra-arterial rt-PA Outcome: 6 Complications- minor haemorrhage

Study or subgroup

Berridge 1991

i.a. streptokinase

i.a. rt-PA

Odds Ratio

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

M-H,Fixed,95% CI

3/20

0/20

8.20 [ 0.40, 169.90 ]

0.01

0.1

Favours i.a.strept.

Fibrinolytic agents for peripheral arterial occlusion (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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10

100

Favours i.a.rt-PA

27

Analysis 3.1. Comparison 3 Intra-arterial urokinase versus intra-arterial rt-PA, Outcome 1 Vessel patency immediately post lysis. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 3 Intra-arterial urokinase versus intra-arterial rt-PA Outcome: 1 Vessel patency immediately post lysis

Study or subgroup

i.a. urokinase

i.a. rt-PA

n/N

n/N

55/110

77/124

0.61 [ 0.36, 1.03 ]

Meyerovitz 1990

6/16

8/16

0.60 [ 0.15, 2.45 ]

Schweizer 1996

44/60

51/60

0.49 [ 0.20, 1.21 ]

Mahler 2001

Odds Ratio

Odds Ratio

M-H,Fixed,95% CI

0.01

0.1

Favours i.a. rt-PA

1

10

M-H,Fixed,95% CI

100

Favours i.a. urokinase

Analysis 3.2. Comparison 3 Intra-arterial urokinase versus intra-arterial rt-PA, Outcome 2 Limb salvage. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 3 Intra-arterial urokinase versus intra-arterial rt-PA Outcome: 2 Limb salvage

Study or subgroup

i.a. urokinase

i.a. rt-PA

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

107/110

113/124

38.5 %

3.47 [ 0.94, 12.79 ]

Meyerovitz 1990

13/16

14/16

34.9 %

0.62 [ 0.09, 4.32 ]

Schweizer 1996

48/50

51/52

26.6 %

0.47 [ 0.04, 5.36 ]

176

192

100.0 %

1.68 [ 0.68, 4.15 ]

Mahler 2001

Total (95% CI)

Weight

Odds Ratio M-H,Fixed,95% CI

Total events: 168 (i.a. urokinase), 178 (i.a. rt-PA) Heterogeneity: Chi2 = 3.26, df = 2 (P = 0.20); I2 =39% Test for overall effect: Z = 1.12 (P = 0.26) Test for subgroup differences: Not applicable

0.001 0.01 0.1 Favours i.a. urokin.

1

10 100 1000 Favours i.a. rt-PA

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Analysis 3.3. Comparison 3 Intra-arterial urokinase versus intra-arterial rt-PA, Outcome 3 Major amputation at 30 days-6 months. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 3 Intra-arterial urokinase versus intra-arterial rt-PA Outcome: 3 Major amputation at 30 days-6 months

Study or subgroup

i.a. urokinase

i.a. rt-PA

n/N

n/N

3/110

11/124

0.29 [ 0.08, 1.06 ]

Meyerovitz 1990

3/16

2/16

1.62 [ 0.23, 11.26 ]

Schweizer 1996

2/50

1/52

2.13 [ 0.19, 24.20 ]

Mahler 2001

Odds Ratio

Odds Ratio

M-H,Fixed,95% CI

0.001 0.01 0.1 Favours i.a. urokin.

1

M-H,Fixed,95% CI

10 100 1000 Favours i.a. rt-PA

Analysis 3.4. Comparison 3 Intra-arterial urokinase versus intra-arterial rt-PA, Outcome 4 Death. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 3 Intra-arterial urokinase versus intra-arterial rt-PA Outcome: 4 Death

Study or subgroup

i.a. urokinase

i.a. rt-PA

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

4/110

6/124

Meyerovitz 1990

0/16

0/16

Schweizer 1996

1/50

1/52

15.0 %

1.04 [ 0.06, 17.11 ]

176

192

100.0 %

0.79 [ 0.24, 2.54 ]

Mahler 2001

Total (95% CI)

Weight

Odds Ratio M-H,Fixed,95% CI

85.0 %

0.74 [ 0.20, 2.70 ] Not estimable

Total events: 5 (i.a. urokinase), 7 (i.a. rt-PA) Heterogeneity: Chi2 = 0.05, df = 1 (P = 0.83); I2 =0.0% Test for overall effect: Z = 0.40 (P = 0.69) Test for subgroup differences: Not applicable

0.001 0.01 0.1 Favours i.a. urokin.

1

10 100 1000 Favours i.a. rt-PA

Fibrinolytic agents for peripheral arterial occlusion (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Analysis 3.5. Comparison 3 Intra-arterial urokinase versus intra-arterial rt-PA, Outcome 5 Complications major haemorrhage. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 3 Intra-arterial urokinase versus intra-arterial rt-PA Outcome: 5 Complications - major haemorrhage

Study or subgroup

i.a. urokinase

i.a. rt-PA

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

0/110

1/124

23.7 %

0.37 [ 0.02, 9.24 ]

Meyerovitz 1990

3/16

5/16

68.6 %

0.51 [ 0.10, 2.62 ]

Schweizer 1996

1/16

0/16

7.7 %

3.19 [ 0.12, 84.43 ]

142

156

100.0 %

0.68 [ 0.19, 2.40 ]

Mahler 2001

Total (95% CI)

Weight

Odds Ratio M-H,Fixed,95% CI

Total events: 4 (i.a. urokinase), 6 (i.a. rt-PA) Heterogeneity: Chi2 = 1.11, df = 2 (P = 0.57); I2 =0.0% Test for overall effect: Z = 0.60 (P = 0.55) Test for subgroup differences: Not applicable

0.001 0.01 0.1 Favours i.a. urokin.

1

10 100 1000 Favours i.a. rt-PA

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Analysis 3.6. Comparison 3 Intra-arterial urokinase versus intra-arterial rt-PA, Outcome 6 Complications minor haemorrhage. Review:

Fibrinolytic agents for peripheral arterial occlusion

Comparison: 3 Intra-arterial urokinase versus intra-arterial rt-PA Outcome: 6 Complications - minor haemorrhage

Study or subgroup

i.a. urokinase

i.a. rt-PA

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

2/110

3/124

20.6 %

0.75 [ 0.12, 4.55 ]

Meyerovitz 1990

0/16

2/16

18.0 %

0.18 [ 0.01, 3.97 ]

Schweizer 1996

5/60

9/60

61.4 %

0.52 [ 0.16, 1.64 ]

186

200

100.0 %

0.50 [ 0.20, 1.26 ]

Mahler 2001

Total (95% CI)

Weight

Odds Ratio M-H,Fixed,95% CI

Total events: 7 (i.a. urokinase), 14 (i.a. rt-PA) Heterogeneity: Chi2 = 0.62, df = 2 (P = 0.73); I2 =0.0% Test for overall effect: Z = 1.47 (P = 0.14) Test for subgroup differences: Not applicable

0.001 0.01 0.1

1

Favours i.a. urokin.

10 100 1000 Favours i.a. rt-PA

APPENDICES Appendix 1. CENTRAL search strategy

#1

MeSH descriptor: [Thrombolytic Therapy] explode all trees

1556

#2

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

#3

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

#4

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

#5

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

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(Continued)

#6

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

#7

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

954

#8

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

53

#9

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

691

#10

plasminogen near/2 activator

3004

#11

clot near/3 (bust* or break* or remov*):ti,ab,kw (Word varia- 54 tions have been searched)

#12

thrombolysis

#13

#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or 6691 #11 or #12

#14

MeSH descriptor: [Arteriosclerosis] this term only

893

#15

MeSH descriptor: [Arteriolosclerosis] this term only

0

#16

MeSH descriptor: [Arteriosclerosis Obliterans] this term only 71

#17

MeSH descriptor: [Atherosclerosis] this term only

#18

MeSH descriptor: [Arterial Occlusive Diseases] this term only 755

#19

MeSH descriptor: [Intermittent Claudication] this term only 711

#20

MeSH descriptor: [Ischemia] this term only

#21

MeSH descriptor: [Peripheral Vascular Diseases] explode all 2150 trees

#22

MeSH descriptor: [Vascular Diseases] this term only

#23

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

#24

MeSH descriptor: [Femoral Artery] explode all trees

720

#25

MeSH descriptor: [Popliteal Artery] explode all trees

250

#26

MeSH descriptor: [Iliac Artery] explode all trees

151

2457

382

753

381

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(Continued)

#27

MeSH descriptor: [Tibial Arteries] explode all trees

29

#28

(atherosclero* or arteriosclero* or PVD or PAOD or PAD)

17195

#29

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

#30

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

#31

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

#32

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

#33

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

#34

(peripheral near/3 (dis* or thrombo*))

3349

#35

arteriopathic

10

#36

(claudic* or hinken*)

1436

#37

(isch* or CLI)

16827

#38

dysvascular*

14

#39

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

#40

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

#41

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

#42

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

#43

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

#44

#14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or # 39771 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 #43

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(Continued)

#45

#13 and #44 in Trials

1996

WHAT’S NEW Last assessed as up-to-date: 21 March 2013.

Date

Event

Description

10 October 2013

New citation required but conclusions have not Searches re-run. No new included studies and one adchanged ditional excluded study were identified. No change to conclusions. Minor edits made

10 October 2013

New search has been performed

Searches re-run. No new included studies and one additional excluded study were identified

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

SOURCES OF SUPPORT Internal sources • No sources of support supplied

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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 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 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

Fibrinolytic agents for peripheral arterial occlusion (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Fibrinolytic agents for peripheral arterial occlusion.

Peripheral arterial thrombolysis is used in the management of peripheral arterial ischaemia. Streptokinase was originally used but safety concerns led...
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