Surgery versus thrombolysis for initial management of acute limb ischaemia

  • Review
  • Intervention

Authors


Abstract

Background

Peripheral arterial thrombolysis is technique used in the management of peripheral arterial ischaemia. Much is known about the indications, risks and benefits of thrombolysis. However, it is not known whether thrombolysis works better than surgery in the initial treatment of acute limb ischaemia.

Objectives

To determine the preferred initial treatment, surgery or thrombolysis, for acute limb ischaemia.

Search methods

For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched March 2013) and CENTRAL (2013, Issue 2).

Selection criteria

All randomised studies comparing thrombolysis and surgery for the initial treatment of acute limb ischaemia.

Data collection and analysis

Each author independently assessed trial quality and extracted data. Agreement was reached by consensus.

Main results

Five trials with a total of 1283 participants were included. There was no significant difference in limb salvage or death at 30 days, six months or one year between initial surgery and initial thrombolysis. However, stroke was significantly more frequent at 30 days in thrombolysis participants (1.3%) compared to surgery participants (0%) (Odds ratio (OR) 6.41; 95% confidence interval (CI) 1.57 to 26.22). Major haemorrhage was more likely at 30 days in thrombolysis participants (8.8%) compared to surgery participants (3.3%) (OR 2.80; 95% CI 1.70 to 4.60); and distal embolization was more likely at 30 days in thrombolysis participants (12.4%) compared to surgery participants (0%) (OR 8.35; 95% CI 4.47 to 15.58).

Participants treated by initial thrombolysis underwent a less severe degree of intervention (OR 5.37; 95% CI 3.99 to 7.22) and displayed equivalent overall survival compared to initial surgery (OR 0.87; 95% CI 0.61 to 1.25).

Authors' conclusions

Universal initial treatment with either surgery or thrombolysis cannot be advocated on the available evidence. There is no overall difference in limb salvage or death at one year between initial surgery and initial thrombolysis. Thrombolysis may be associated with a higher risk of ongoing limb ischaemia and haemorrhagic complications including stroke. The higher risk of complications must be balanced against risks of surgery in each person.

摘要

背景

比較手術與血栓溶解法來進行急性下肢缺血的初步治療

周邊動脈血栓溶解法(thrombolysis)是一種用在治療周邊動脈缺血的技術,對血栓溶解療法的適應症、風險和效益已經有了較多的了解,但是目前仍無法得知血栓溶解療法對於急性下肢缺血的初步治療結果上是不是比手術療法具有更好的成效。

目標

對於急性下肢缺血之初步治療,決定手術或血栓溶解法合者為佳。

搜尋策略

搜尋Cochrane Peripheral Vascular Diseases Group's Specialized Register (最後一次搜尋為 2007年2月) 及Cochrane Library 的Cochrane Central Register of Controlled Trials (CENTRAL) (創刊到Issue 1, 2007年)。搜尋所有來自英國血管外科學會、歐洲血管外科學會and 北美血管外科學會、心臟血管及介入放射學會(SCVIR) and 歐洲心臟血管及介入學會(CIRSE)的研討會資料。並聯絡藥廠以及試驗研究人員以取得未發表的試驗。

選擇標準

所有比較手術療法或血栓溶解療法對急性下肢缺血初步治療效果的隨機性研究。

資料收集與分析

每一個作者獨自評估試驗品質和萃取數據,利用協商達成一致性的意見。

主要結論

有包含了1283名受試者的5個試驗被納入,使用手術或血栓溶解方法進行初步治療,對於保住肢體或第30天、6個月或1年的死亡率等預後上並沒有產生顯著差異。但是在血栓溶解組,在30天內出現中風症狀的患者(1.3%)明顯多於接受手術治療組(0%)(OR值為6.41,95% CI值介於1.57至26.22間)。且在30天內,血栓溶解組出現大量出血的病患(8.8%)也多於手術治療組(3.3%)(OR值為2.80,95% CI值介於1.70至4.60間)。且血栓溶解的組別中,出現遠端栓塞的病患(12.4%)也多於手術治療組的病患(0%) (OR值為8.35,95% CI值介於4.47至15.58間)。以血栓溶解為初始治療方法的病患受到介入治療的程度較低(OR值為5.37,95% CI值介於3.99至7.22間),整體存活率與以手術為初始治療者相同(OR值為0.87,95% CI值介於0.61至1.25間)。

作者結論

根據現有的證據不能主張以手術療法或血栓溶解療法為通用的初始療法,這兩種方法對於肢體保存或是第一年的死亡率整體來說並無差別。血栓溶解療法可能和進行性之肢體缺血和出血併發症(包括中風)有關。對於每一個病患,應該評估產生併發症的風險和手術的風險,加以平衡。

翻譯人

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

比較手術與血栓溶解法來進行急性下肢缺血的初步治療。 血栓溶解是將酵素注射至血塊處以溶解血塊的方法,這是一種用來處理腿部血流嚴重減少(急性缺血)時替代手術的療法。在腿部血管形成的血塊(栓塞)會使得天然的動脈或是人工的導管出現嚴重狹窄。 本回顧的作者確認了5個對照性試驗,並將1283名急性下肢缺血之病患,隨機分配接受周邊動脈血栓溶解或是手術為初始療法。 對於防止需要進行截肢(肢體保留)或第一年內死亡率的項目上,並沒有證據傾向於應該要使用血栓溶解或是手術。但是進行血栓溶解療法時,30天內出現重大併發症的情形較為常見,這些併發症包括了中風和大量出血,大約有1.3%接受血栓溶解治療的病患出現中風的症狀,但手術治療患者中並沒有人中風,且有8.8%的患者在進行血栓溶解治療後出現大量出血的狀況,手術治療組出現大量出血的比例則為3.3%。以血栓溶解治療為初始療法的病患雖然受到較低程度的介入治療,但是卻可能具有較高的風險會出現進行中之肢體缺血的現象。 使用血栓溶解療法出現併發症的風險應該要和進行手術治療的風險進行權重衡量。 重組之組織胞漿素活化劑(tissue plasminogen activator)或是urokinase都是血栓溶解療法所使用的藥劑。

Résumé scientifique

Chirurgie versus thrombolyse pour le traitement initial d'une ischémie aiguë des membres inférieurs

Contexte

La thrombolyse artérielle périphérique est une technique utilisée pour traiter l'ischémie artérielle périphérique. On en sait beaucoup à propos des indications, des risques et des avantages de la thrombolyse. Toutefois, on ne sait pas si la thrombolyse fonctionne mieux que la chirurgie dans le traitement initial d'une ischémie aiguë des membres inférieurs.

Objectifs

Déterminer le traitement initial préféré, chirurgie ou thrombolyse, pour l'ischémie aiguë des membres inférieurs.

Stratégie de recherche documentaire

Le groupe Cochrane sur les maladies vasculaires périphériques a effectué une recherche dans son propre registre spécialisé (dernière recherche en janvier 2009) et dans le registre Cochrane des essais contrôlés (CENTRAL) dans The Cochrane Library (dernière recherche dans le numéro 1, 2009). Des recherches manuelles ont été effectuées dans les actes de conférence de la British Vascular Surgical Society, la European Vascular Surgical Society et la North American Society of Vascular Surgery, la Society of Cardiovascular and Interventional Radiology (SCVIR) et la Cardiovascular and Interventional Society of Europe (CIRSE). Les entreprises pharmaceutiques et les listes d'essais ont été questionnées pour obtenir des informations sur les essais non publiés.

Critères de sélection

Toutes les études randomisées comparant la thrombolyse et la chirurgie pour le traitement initial de l'ischémie aiguë des membres inférieurs.

Recueil et analyse des données

Chaque auteur a extrait les données et évalué la qualité des essais de manière indépendante. Un accord a été atteint par consensus.

Résultats principaux

Cinq essais, totalisant 1 283 participants, ont été inclus. Il n'a été constaté aucune différence significative dans le sauvetage de la jambe ou dans le décès à 30 jours, six mois ou un an entre la chirurgie initiale et la thrombolyse initiale. Pour autant, l'AVC était bien plus fréquent à 30 jours chez les participants avec thrombolyse (1,3 %) par rapport aux participants avec chirurgie (0 %) (rapport des cotes 6,41 ; intervalle de confiance (IC) à 95 % 1,57 à 26,22). Une hémorragie importante était plus probable à 30 jours chez les participants avec thrombolyse (8,8 %) par rapport aux participants avec chirurgie (3,3 %) (rapport des cotes 2,80 ; IC à 95 % 1,70 à 4,60) ; et une embolisation distale était plus probable à 30 jours chez les participants avec thrombolyse (12,4 %) par rapport aux participants avec chirurgie (0 %) (rapport des cotes 8,35 ; IC à 95 % 4,47 à 15,58).

Les participants traités par une thrombolyse initiale ont subi un degré moins important d'intervention (rapport des cotes 5,37 ; IC à 95 % 3,99 à 7,22) et ont présenté une survie globale équivalente par rapport à la chirurgie initiale (rapport des cotes 0,87 ; IC à 95 % 0,61 à 1,25).

Conclusions des auteurs

Le traitement initial universel avec chirurgie ou thrombolyse ne peut pas être préconisé compte tenu des preuves disponibles. Il n'existe aucune différence globale dans le sauvetage de la jambe ou dans le décès après un an entre la chirurgie initiale et la thrombolyse initiale. La thrombolyse peut être associée à un risque accru d'ischémie des membres inférieurs et à des complications hémorragiques, y compris un AVC. Le risque plus élevé de complications doit être mise en balance avec les risques liés à la chirurgie pour chaque personne.

Plain language summary

Surgery versus thrombolysis for initial management of acute limb ischaemia

Thrombolysis involves dissolving a blood clot by injecting an enzyme into the blood clot. It is used as an alternative to surgery for managing severely reduced blood flow (acute ischaemia) in the leg. A blood clot (thrombosis) forms in a leg blood vessel where there is severe narrowing (stenosis) in a natural artery or a bypass graft.

The review authors identified five controlled trials with a total of 1283 participants who were randomly allocated to receive initial peripheral arterial thrombolysis or surgery for the immediate management of acute limb ischaemia. There was no evidence in favour of either initial thrombolysis or initial surgery as the preferred option in terms of preventing the need for major amputation (limb salvage) or death within one year. More major complications occurred within 30 days of the procedure with thrombolysis, including stroke and major bleeding (haemorrhage). A total of 1.3% of patients receiving thrombolysis had a stroke compared to none in surgery patients; 8.8% had a major haemorrhage after thrombolysis compared to 3.3% in surgery patients. People receiving initial thrombolysis underwent a less severe degree of intervention but may have a higher risk of ongoing limb ischaemia. These higher risks of complications with thrombolysis have to be weighted against individual risks in surgery. Either recombinant tissue plasminogen activator or urokinase were the agents used for thrombolysis.

Résumé simplifié

Chirurgie versus thrombolyse pour le traitement initial d'une ischémie aiguë des membres inférieurs

La thrombolyse consiste à dissoudre un caillot de sang par l'injection d'une enzyme dans le caillot. Elle est utilisée comme alternative à la chirurgie pour gérer un flux sanguin réduit (ischémie aiguë) dans la jambe. Un caillot de sang (thrombose) se forme dans un vaisseau sanguin de la jambe où il génère un rétrécissement important (sténose) d'une artère naturelle ou d'un greffon de pontage.

Les auteurs de la revue ont identifié cinq essais contrôlés totalisant 1 283 participants qui ont été répartis de manière aléatoire pour recevoir une thrombolyse artérielle périphérique initiale ou une chirurgie afin de traiter immédiatement une ischémie aiguë des membres inférieurs. Il n'a été trouvé aucune preuve en faveur de la thrombolyse initiale ou de la chirurgie initiale comme option préférée en termes de prévention du besoin d'une amputation majeure (sauvetage de la jambe) ou du décès au bout d'un an. Des complications plus importantes surviennent dans les 30 jours de la procédure avec thrombolyse, y compris un accident vasculaire cérébral (AVC) ou des saignements graves (hémorragie). Un total de 1,3 % des patients recevant la thrombolyse ont eu un AVC par rapport à aucun chez les patients sous chirurgie ; 8,8 % ont eu une hémorragie grave par rapport à 3,3 % chez les patients avec chirurgie. Les personnes recevant une thrombolyse initiale ont subi un degré moins grave d'intervention mais peuvent avoir un risque plus élevé d'ischémie des membres inférieurs en cours. Ces
risques plus élevés de complications avec la thrombolyse doivent être mis en balance avec les risques individuels de la chirurgie. Les agents utilisés pour la thrombolyse étaient soit un activateur tissulaire du plasminogène recombinant, soit de l'urokinase.

Notes de traduction

Cette revue est la première de trois revues concernant les différents aspects de la thrombolyse, toutes seront couvertes par le protocole générique 'Chirurgie versus thrombolyse pour l'ischémie aiguë des membres inférieurs', ID unique 031499080512564323.La seconde revue s'intitule 'Techniques de perfusion pour la thrombolyse artérielle périphérique'. La troisième revue s'intitule 'Agents fibrinolytiques pour l'occlusion artérielle périphérique'.

Traduit par: French Cochrane Centre 6th December, 2012
Traduction financée par: Minist�re des Affaires sociales et de la Sant�

Background

Peripheral arterial thrombolysis is a useful technique in the management of peripheral arterial ischaemia. Much is known about the indications, risks and benefits of thrombolysis, although data from randomised controlled studies are limited. The management of the acutely ischaemic leg has traditionally been the domain of the surgeon and, with increasing specialisation, the vascular surgeon. The optimal initial management of the acutely ischaemic leg needs to be determined.

In 1963, introduction of the thromboembolectomy catheter (a flexible tube through which thrombus is extracted) allowed large amounts of thromboembolic material to be removed rapidly to restore blood flow to ischaemic areas. However, the nature of the underlying disease process has changed since then. Whilst emboli used to be the most likely cause of a sudden deterioration in limb perfusion, this is now more likely to be caused by thrombosis at a site of underlying severe stenosis (narrowing of the vessel). The use of a thromboembolectomy catheter under these circumstances is more likely to exacerbate, rather than relieve, the situation. Furthermore, acute thrombosis of peripheral arterial bypass grafts is also an important cause of acute ischaemia and the sensitive endothelial lining of vein grafts may be easily denuded (stripped off) by a thromboembolectomy catheter. In addition, up to 30% of thromboembolectomies may show residual thrombus on angiogram (Plecha 1972).

Peripheral arterial thrombolysis, involving the localised infusion of an enzyme to dissolve the clot, potentially allows the preservation of endothelium, the accurate localisation of any underlying aetiological factor causing thrombosis, and its correction either percutaneously (through the skin), or by a more limited directed surgical approach. However, this may be at the risk of a greater incidence of major haemorrhage and stroke. Direct comparison between initial thrombolysis and initial surgery has now been addressed by a number of randomised trials.

Objectives

To determine whether thrombolysis or surgery is the more effective technique in the initial management of acute limb ischaemia. The specific hypotheses to be tested were:

1) there are advantages in terms of limb salvage and survival dependent upon whether thrombolysis or surgery is used in the initial management of acute limb ischaemia; and
2) there is a reduction in the eventual level of intervention required dependent upon whether thrombolysis or surgery is used in the initial management of acute limb ischaemia.

Methods

Criteria for considering studies for this review

Types of studies

This review included trials in which participants were randomly allocated to receive initial peripheral arterial thrombolysis or initial surgery for the immediate management of acute limb ischaemia.

Types of participants

Participants presented with acute or acute-on-chronic limb ischaemia following a thromboembolic occlusion of either a native peripheral artery or a thrombosed lower limb graft, dialysis access excluded. Participants were included irrespective of diabetic status, use of aspirin or anticoagulation post-thrombolysis, or use of concurrent heparin.

Types of interventions

The review concentrates on the initial management with either peripheral arterial thrombolysis or surgery. Subsequent interventions required, or performed, were noted. All thrombolytic agents were considered.

Types of outcome measures

Primary outcomes
  1. Limb salvage (i.e. avoidance of a major amputation)

Secondary outcomes
  1. Amputation

  2. Death

  3. Vessel patency

  4. Time to lysis

  5. Complications including major haemorrhage, strokes, distal embolization

  6. Reduction in the need for intervention (i.e. a more limited, and potentially less risky, treatment was then possible)

Search methods for identification of studies

Electronic searches

2013 update 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 2, 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

2001 searches

We reviewed reference lists of papers resulting from this search. We handsearched proceedings from the following meetings for relevant trials: Vascular Surgical Society of Great Britain and Ireland (1986 to 2001); European Vascular Surgical Society (1990 to 2001); Surgical Research Society (1988 to 2001); Mosby Vascular Surgery Yearbook (1996 to 2001); The Society for Vascular Surgery (1995 to 2001). We asked all major pharmaceutical firms about unpublished trials that met the criteria described above. We also asked authors of published trials if they were aware of any relevant unpublished trials.

Data collection and analysis

Selection of studies

The selection of trials for inclusion in this review was carried out independently by each of the three authors. One author (DCB) identified all possible trials and sent these to the other authors (DK/IR). We resolved discrepancies by discussion. The criteria for selection of trials were as specified in the above section Criteria for considering studies for this review.

Data extraction and management

Data collected from each trial included information on participants' age, sex distribution, severity of disease as measured by ankle brachial pressure index (ABPI) and the European Consensus definition of critical ischaemia (Consensus Document), Fontaine classification (Fontaine 1954), and Ad Hoc Committee Recommendations (Reporting Standards). Where possible, limb salvage, vessel or graft patency, amputation, death and complications were recorded.

Assessment of risk of bias in included studies

The methodological quality of each trial was assessed independently using the checklist provided by the Cochrane Peripheral Vascular Diseases Review Group with emphasis on concealment of randomisation. Each author gave an allocation of score of A (clearly concealed), B (unclear if concealed) or C (clearly not concealed), and a summary score of A (low risk of bias) or C (high risk of bias). Trials scoring B were discussed and attempts made to obtain further information from the authors. Discrepancies were resolved by discussion.

Measures of treatment effect

We synthesised the data by comparing group results. We did not combine individual patient data from different trials. We used subjective clinical judgement, and where possible, objective testing, to assess heterogeneity between trials.

Sensitivity analysis

We did not carry out sensitivity analyses.

Results

Description of studies

We found five prospective randomised controlled studies comparing initial thrombolysis with initial surgery in the management of acute limb ischaemia (Nilsson 1992; Ouriel 1994; Ouriel 1996; Ouriel 1998a; STILE 1994). Major differences in participant demographics, including severity of ischaemia, site of occlusion, prosthetic or native vessel, thrombolytic regime and agent, requires caution in interpreting meta-analysis of the data. We have also included two further publications from the STILE trial looking at native vessel occlusions (Weaver 1996), and bypass graft occlusions (Comerota 1996) and one further publication from the Ouriel 1998a trial (Ouriel 1998b).

Follow-up was variable, from one month (Nilsson 1992) to one year (Comerota 1996; Ouriel 1994; Ouriel 1996; Ouriel 1998a; STILE 1994; Weaver 1996). See the Characteristics of included studies for further details.

Note: The STILE trial (Comerota 1996; STILE 1994; Weaver 1996) was stopped early because of an excess of complications in the thrombolysis group.

There were two studies which were excluded (Patel 1999; Tiek 2009), one of which was added in the 2013 update (Tiek 2009).

Risk of bias in included studies

The Nilsson trial (Nilsson 1992) was awarded a B grade for methodological quality, but all the other trials (Ouriel 1994; Ouriel 1996; Ouriel 1998a; STILE 1994), and additional papers from those trials (Comerota 1996; Ouriel 1998b; Weaver 1996) were awarded A grades.

All studies were randomised using telephone computerised randomisation with the exception of Nilsson 1992 (not actually stated). Due to the nature of the study, neither participants nor observers were blinded.

All studies were reported as intention-to-treat (ITT). The STILE trial (Comerota 1996; STILE 1994; Weaver 1996) also reported as per-protocol. Intention-to-treat includes analysis of all participants according to the treatment allocated by the randomisation procedure, regardless of whether they actually received that particular treatment. Per-protocol analysis was performed on the two groups of participants that actually received the two different treatments.

Duration of ischaemia requiring intervention was less than 14 days in Nilsson 1992, Ouriel 1996 and Ouriel 1998a. However, Ouriel 1994 used less than seven days of ischaemia as criteria for intervention. The STILE trial (Comerota 1996; STILE 1994; Weaver 1996), admitted participants with "signs or symptoms of worsening limb ischaemia within the past six months who required intervention" or who had a bypass graft occlusion.

Effects of interventions

The concept of a reduced level of procedure required was used in the STILE and Ouriel trials. This consists of a list of interventional procedures in order of increasing severity of intervention. Hence, if thrombolytic treatment were successful, it could be argued that the reduced need for further intervention would be less hazardous to the participant.

Nilsson 1992
In this study, a total of 20 participants were randomised to thrombolysis (n = 11) with recombinant tissue plasminogen activator (rt-PA) infused over a three hour period, or to surgical thrombectomy (n = 9). There were no strokes or major haemorrhages with either thrombolysis or surgery at 30 days. Furthermore, there were no deaths or amputations in the thrombolytic group at 30 days, though there was one death and one amputation in the surgery group. Only four participants had successful thrombolysis with continued patency at one month. Three participants required a femoro-distal graft and two required thromboembolectomy. However, such small numbers hinder any firm conclusions from being drawn from this study.

Ouriel 1994
In this trial, 114 participants were randomised to surgery (revascularisation or amputation, as required; n = 57) or to thrombolysis with urokinase (n = 57). At the 12 month follow-up (Ouriel 1994) there was a significant survival advantage of initial thrombolysis (84%) compared to initial surgery (58%; P = 0.01) (Peto odds ratio (OR) 0.28; 95% CI 0.13 to 0.63). This was thought to be due principally to the difference in in-hospital cardio-pulmonary complications between the two groups (thrombolysis group 16%; surgery group 41%; P = 0.001). There was no difference in limb salvage. At 30 days the stroke rate was 1.8% (n = 1) and major haemorrhage rate was 10.5% (n = 6) in the thrombolysis group, compared to no strokes (n = 0) and a rate of major haemorrhage of 1.8% (n = 1) in the surgical group. Thirty-six percent of participants in the thrombolytic therapy group had continued patency at 12 months.

STILE 1994
The STILE trial (STILE 1994) recruited 393 participants from 31 centres (follow up information was available for 392 participants) to compare surgery against thrombolysis in the initial treatment of limb ischaemia. It should be noted that two different thrombolytic regimes were used (see the Characteristics of included studies table). The trial included participants with a duration of ischaemia of up to six months. It was originally anticipated that interim analyses would be performed at 300 and 600 participants. However, the data monitoring committee stopped the trial at 393 participants due to a higher incidence of adverse events (Composite Clinical Outcome P = 0.011) in the thrombolytic group at one month. This was similar in both native artery and bypass graft subgroups at one month.

Composite Clinical Outcome was a combination of outcomes including: ongoing or recurrent ischaemia, death or major amputation (above or below-knee), life-threatening haemorrhage (hypotension, requiring resuscitation), or stroke, peri-intervention complications such as myocardial infarction, pulmonary oedema, renal failure requiring dialysis, serious anaesthetic complications, vascular complications and post-operative wound complications.

There was a significantly reduced level of the procedure required in the thrombolysis group compared to the surgical group (55.8% versus 5.5%; P = 0.001). At six months, those in the thrombolysis group with less than 14 days ischaemia had a significantly reduced rate of death or amputation, or both (15.3% versus 37.5%; P = 0.01) (OR 0.29; 95% CI 0.12 to 0.72). For those with more than 14 days duration, a reversed trend was seen (death/amputation rate 9.9% in the surgical group versus 17.8% in the thrombolysis group), a difference which failed to reach significance (P = 0.08). Stroke occurred in 1.2% of participants receiving thrombolysis, while major haemorrhage occurred in 5.6%. In the surgical group haemorrhage occurred in 0.7%. Catheter placement failed in 28% of participants randomised to receive thrombolysis - a high technical failure rate, which potentially limits its widespread application. However, the study group may be unrepresentative.

Subsequent subgroup analysis by the trialists of those participants less than 14 days and those more than 14 days duration of ischaemia suggested alternative interpretations, although there had been no initial stratification in the randomisation protocol to allow for this. Participants with more than 14 days duration of history fared better (Composite Clinical Outcome) with surgery than with initial thrombolysis (P < 0.001). For participants with less than 14 days duration of ischaemia there was no difference in overall Composite Clinical Outcome (P = 0.439), but there were more amputations in the surgical group (17.9% versus 5.7%; P = 0.061).

The 12 month follow-up data on bypass grafts were reported by Comerota (Comerota 1996), and the native artery results by Weaver (Weaver 1996).

Comerota 1996
Further subgroup analysis resulted in low numbers of participants in each sub-group. For example, analysis by duration of history less than 14 days reduced numbers to 35 in the thrombolysis group and 23 in the surgical group. A similar advantage of a reduced amputation rate demonstrated in the original STILE study was again seen in the less than 14 day thrombolysis group. Overall however, thrombolysis was associated with a higher level of continued ischaemia, claudication or critical limb ischaemia (73% versus 50%; P = 0.01) (OR 2.72; 95% CI 1.2 to 5.80). Those participants with ischaemia for more than 14 days were associated with a significantly increased risk of ongoing or recurrent ischaemia. Significantly increased morbidity was encountered with prosthetic grafts compared to autogenous grafts (P = 0.038). While no difference was found between supra-inguinal and infra-inguinal grafts, it should be noted that there were only 22 (38%) grafts in the supra-inguinal group.

Weaver 1996
The native artery 12 month results confirmed a reduction in the surgical procedure required in approximately 50% of those participants randomised to thrombolysis (i.e. 50% of those participants receiving thrombolysis were able to undergo a more limited procedure than would have been expected prior to thrombolysis). However, at one year both recurrent ischaemia and major amputation were significantly higher in the thrombolysis group (recurrent ischaemia 64% versus 35%; P < 0.0001) (OR 3.26; 95% CI 1.92 to 5.52), major amputation 10% versus 0% (P = 0.0024). Stratification looking at ilio-femoral/femoro-popliteal and less than 14 days or more than 14 days duration of history all served to reduce the numbers in each group to as low as n = 4 in one instance.

The STILE trial papers (Comerota 1996; STILE 1994; Weaver 1996) all reported ITT but also per protocol analyses. There was a high percentage of participants classified as 'thrombolysis', who never actually received thrombolysis, after failure to site the catheter.

One of the major criticisms of the STILE publications was that the less than 14 days or more than 14 days analysis was a post-hoc arbitrary division, not a stratified part of the original protocol. Over 80% of all participants had a more than 14 days duration of history.

Ouriel 1996
This paper (Ouriel 1996) reports the early experience of the TOPAS group (The Study of Thrombolysis Or Peripheral Arterial Surgery). Seventy-nine participating centres enrolled 213 participants over approximately six months. Participants had Class II ischaemia for less than 14 days (Reporting Standards). Three different urokinase thrombolysis regimes were used - 2000 IU/min, 4000 IU/min or 6000 IU/min for the first two hours, after which all groups received 2000 IU/min. The comparison between surgery and thrombolysis was performed with the optimal thrombolysis group (i.e. 4000 IU/min). No overall thrombolysis figures were available. There was no significant difference in the one year mortality rate or amputation-free survival rate between thrombolysis with 4000 IU/min urokinase and the surgical group. All thrombolytic groups had a significant reduction in open surgery compared to the surgery group at 30 days (P = 0.01).

Ouriel 1998a
In this subsequent trial, the 'optimal dose' of urokinase was used (4000 IU/min) as described for Ouriel 1996 above. Five hundred and forty-eight participants from 113 centres throughout the USA and Northern Europe were recruited over a period of 17 months. Although the randomisation was done by telephone, there were significant differences between the treatment groups. There were significantly higher numbers of men, increased hepatic or renal insufficiency, or both, and increased rest pain at presentation in the thrombolysis group. Death at one year was similar between the two groups (thrombolysis = 20%; surgery = 17%) and there was no significant difference in limb salvage (thrombolysis = 65%; surgery = 69.9%). At 30 days four (1.6%) strokes had occurred in the thrombolytic group, but none in the surgery group. Major haemorrhage was significantly higher in the thrombolysis group at 30 days (12.5% versus 5.5%; P = 0.005) (OR 2.35; 95% CI 1.28 to 4.29). Open surgical procedures were significantly lower in the thrombolysis group compared to the surgical group at six months (54% versus 91% respectively; P < 0.001).

Ouriel 1998b
Using the TOPAS database, the authors found in a univariate analysis that amputation-free survival was associated with race (69.4% white versus 60.0% non-white); age (75.1% less than 65 years versus 60.2% greater than 65 years); body weight (60.5% less than 160 lb versus 73.5% greater than 160 lb); history of central nervous system disease (70.6% history versus 51.15 with no history); history of congestive heart failure (70.7% history versus 46.1% with no history); mottled or cyanotic skin (72.7% mottled or cyanotic versus 58.3% normal) and presence of rest pain (80.1% rest pain versus 62.9% no rest pain). All these were significant at the 5% level.

Meta-analysis
Meta-analysis of the included trials showed no significant difference in limb salvage or death at 30 days, six months or one year between initial surgery and initial thrombolysis. Stroke was significantly more likely to occur with initial thrombolysis at 30 days. There were eight strokes in the 640 participants receiving thrombolysis, compared to none in the 540 participants receiving initial surgery (OR 6.41; 95% CI 1.57 to 26.22). Major haemorrhage at 30 days was also more likely within the thrombolysis group, with 52/588 occurrences versus 16/482 occurrences in the surgery group (OR 2.80; 95% CI 1.70 to 4.60). Distal embolization occurred in 42/340 participants receiving thrombolysis, with no reported occurrences in 338 participants undergoing initial surgery (OR 8.35; 95% CI 4.47 to 15.58).

As mentioned above concerning the STILE and Ouriel trials participants treated by initial thrombolysis may undergo a less severe degree of intervention (OR 5.37; 95% CI 3.99 to 7.22), and can expect an equivalent overall survival compared to initial surgery (OR 0.87; 95% CI 0.61 to 1.25). However, they may have a higher incidence of recurrent or ongoing limb ischaemia, major haemorrhage or stroke.

Discussion

There are relatively few trials available to resolve the use of surgery or thrombolysis in the initial treatment of acute limb ischaemia. Clinical heterogeneity, differing reporting methods, and differing thrombolytic agents or techniques all combine to inhibit very close comparison from one trial to another. However, meta-analysis of these trials does show a higher incidence of stroke, major haemorrhage and distal embolization at 30 days in the thrombolysis group. There was no significant difference in limb salvage or death at 30 days, six months, or one year. Improved survival at one year (Ouriel 1994), was not confirmed in a much larger subsequent study (Ouriel 1998a); however, there were important differences in the study population. Subsequent further analysis of the TOPAS data (Ouriel 1998b) suggests a number of variables that might be used in the future selection of those participants most likely to benefit from initial thrombolysis.

Failure to place the catheter was a major problem in the STILE trial (STILE 1994), but this may reflect reality when such a technique is used more universally and when it is applied to more chronic lesions. However, while this may have affected the conclusions from the 'intention-to-treat' analysis, these were not substantially different to the 'per-protocol' analysis that effectively reached similar conclusions.

For both the STILE trial (Comerota 1996; STILE 1994; Weaver 1996), and the Ouriel trials (Ouriel 1996; Ouriel 1998a), the reduction in surgery required after thrombolysis was based on an arbitrary gradation of intervention severity. Whilst not identical, there were close similarities. Less intervention ranged from no intervention or medical treatment, through thrombolysis, endarterectomy or graft revision, new graft placement and ultimately a major amputation, below-knee amputation and then finally above-knee amputation. Whilst the exact positioning of thrombolysis in this list may be considered debatable, it needs to be remembered that there is no overall difference in limb salvage or death at one year, despite the potential higher complications of haemorrhage and stroke with thrombolysis. Continuing ischaemia can be dealt with on an elective basis and not necessarily as an emergency procedure.

We still do not know the precise criteria to recommend for a participant's inclusion in a programme of initial thrombolysis. The cut-off (arbitrarily taken at less than or more than 14 days in the STILE trial), appears to be relatively short, but whether it should really be at seven, 14 or even 30 days remains open to debate.

The reports by Comerota and Weaver (Comerota 1996; Weaver 1996) are post-hoc subgroup analyses of the STILE Trial (STILE 1994). We must therefore exercise caution in interpreting or extrapolating the results and conclusions. Nevertheless, there are some important points which have been discussed that should be considered in the potential design of any future studies.

Authors' conclusions

Implications for practice

There is no evidence in favour of either initial thrombolysis or initial surgery as the preferred option in terms of limb salvage or death at one year, but there is a higher incidence of major complications with thrombolysis, including stroke and major haemorrhage.

Thrombolysis needs to be used only in carefully selected and monitored participants; fully informed consent needs to be obtained. The combined vascular surgical and vascular radiological team looking after the participant should consider the surgical and thrombolytic/endovascular options.

Implications for research

All trials concerning thrombolysis and surgery need to classify and randomise participants according to the Ad Hoc Committee on reporting standards (Reporting Standards). No data exists in support of treating participants with a long duration of symptomatic history. Future trials should look at the use of thrombolysis in those participants who traditionally have been considered suitable for peripheral arterial thrombolysis, i.e. those with a duration of ischaemic history of up to 30 days.

Future studies should also consider the quality of life implications of initial surgery compared to initial thrombolysis management.

Acknowledgements

We thank the Cochrane Peripheral Vascular Diseases Review Group for their assistance with the literature searches. We would also like to thank the Cochrane Consumer Network for providing the Plain Language Summary.

Data and analyses

Download statistical data

Comparison 1. Surgery versus thrombolysis: Limb salvage
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Limb salvage at 30 days4636Peto Odds Ratio (Peto, Fixed, 95% CI)1.21 [0.74, 1.99]
2 Limb salvage at 6 months2546Peto Odds Ratio (Peto, Fixed, 95% CI)0.86 [0.59, 1.26]
3 Limb salvage at 1 year2654Peto Odds Ratio (Peto, Fixed, 95% CI)0.88 [0.62, 1.23]
Analysis 1.1.

Comparison 1 Surgery versus thrombolysis: Limb salvage, Outcome 1 Limb salvage at 30 days.

Analysis 1.2.

Comparison 1 Surgery versus thrombolysis: Limb salvage, Outcome 2 Limb salvage at 6 months.

Analysis 1.3.

Comparison 1 Surgery versus thrombolysis: Limb salvage, Outcome 3 Limb salvage at 1 year.

Comparison 2. Surgery versus thrombolysis: Amputation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Amputation at 30 days3615Peto Odds Ratio (Peto, Fixed, 95% CI)0.97 [0.51, 1.85]
2 Amputation at 6 months1 Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected
3 Amputation at 1 year3768Peto Odds Ratio (Peto, Fixed, 95% CI)1.13 [0.82, 1.55]
Analysis 2.1.

Comparison 2 Surgery versus thrombolysis: Amputation, Outcome 1 Amputation at 30 days.

Analysis 2.2.

Comparison 2 Surgery versus thrombolysis: Amputation, Outcome 2 Amputation at 6 months.

Analysis 2.3.

Comparison 2 Surgery versus thrombolysis: Amputation, Outcome 3 Amputation at 1 year.

Comparison 3. Surgery versus thrombolysis: Death
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death at 30 days4636Peto Odds Ratio (Peto, Fixed, 95% CI)0.58 [0.30, 1.13]
2 Death at 6 months1 Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected
3 Death at 1 year3768Peto Odds Ratio (Peto, Fixed, 95% CI)0.87 [0.61, 1.25]
Analysis 3.1.

Comparison 3 Surgery versus thrombolysis: Death, Outcome 1 Death at 30 days.

Analysis 3.2.

Comparison 3 Surgery versus thrombolysis: Death, Outcome 2 Death at 6 months.

Analysis 3.3.

Comparison 3 Surgery versus thrombolysis: Death, Outcome 3 Death at 1 year.

Comparison 4. Surgery versus thrombolysis: Vessel patency
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Vessel patency at 30 days1 Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected
Analysis 4.1.

Comparison 4 Surgery versus thrombolysis: Vessel patency, Outcome 1 Vessel patency at 30 days.

Comparison 5. Surgery versus thrombolysis: Stroke
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Stroke at 30 days51180Peto Odds Ratio (Peto, Fixed, 95% CI)6.41 [1.57, 26.22]
Analysis 5.1.

Comparison 5 Surgery versus thrombolysis: Stroke, Outcome 1 Stroke at 30 days.

Comparison 6. Surgery versus thrombolysis: Major haemorrhage
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Major haemorrhage at 30 days41070Peto Odds Ratio (Peto, Fixed, 95% CI)2.80 [1.70, 4.60]
Analysis 6.1.

Comparison 6 Surgery versus thrombolysis: Major haemorrhage, Outcome 1 Major haemorrhage at 30 days.

Comparison 7. Surgery versus thrombolysis: Distal embolization
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Distal embolization at 30 days3678Peto Odds Ratio (Peto, Fixed, 95% CI)8.35 [4.47, 15.58]
Analysis 7.1.

Comparison 7 Surgery versus thrombolysis: Distal embolization, Outcome 1 Distal embolization at 30 days.

Comparison 8. Surgery versus thrombolysis: Reduction in level of surgery required
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Reduction in level of surgery required at 30 days31046Peto Odds Ratio (Peto, Fixed, 95% CI)5.37 [3.99, 7.22]
2 Reduction in need for open surgery at 6 months1 Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected
Analysis 8.1.

Comparison 8 Surgery versus thrombolysis: Reduction in level of surgery required, Outcome 1 Reduction in level of surgery required at 30 days.

Analysis 8.2.

Comparison 8 Surgery versus thrombolysis: Reduction in level of surgery required, Outcome 2 Reduction in need for open surgery at 6 months.

Comparison 9. Surgery versus thrombolysis: Combined amputation / death
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Combined amputation / death at 6 months in less than 14 days ischaemia1 Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected
Analysis 9.1.

Comparison 9 Surgery versus thrombolysis: Combined amputation / death, Outcome 1 Combined amputation / death at 6 months in less than 14 days ischaemia.

Comparison 10. Surgery versus thrombolysis: Continuous ischaemia at 1 year
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Native vessels1 Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected
2 Bypass grafts1 Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected
Analysis 10.1.

Comparison 10 Surgery versus thrombolysis: Continuous ischaemia at 1 year, Outcome 1 Native vessels.

Analysis 10.2.

Comparison 10 Surgery versus thrombolysis: Continuous ischaemia at 1 year, Outcome 2 Bypass grafts.

Appendices

Appendix 1. CENTRAL search strategy

#1MeSH descriptor: [Arteriosclerosis] explode all trees and with qualifiers: [Surgery - SU]557
#2MeSH descriptor: [Arteriosclerosis Obliterans] explode all trees and with qualifiers: [Surgery - SU]8
#3MeSH descriptor: [Atherosclerosis] explode all trees and with qualifiers: [Surgery - SU]24
#4MeSH descriptor: [Arterial Occlusive Diseases] explode all trees and with qualifiers: [Surgery - SU]1040
#5MeSH descriptor: [Ischemia] explode all trees and with qualifiers: [Surgery - SU]184
#6MeSH descriptor: [Peripheral Vascular Diseases] explode all trees and with qualifiers: [Surgery - SU]117
#7MeSH descriptor: [Leg] explode all trees and with qualifiers: [Blood supply - BS, Surgery - SU]1226
#8MeSH descriptor: [Femoral Artery] explode all trees and with qualifiers: [Surgery - SU]230
#9MeSH descriptor: [Popliteal Artery] explode all trees and with qualifiers: [Surgery - SU]129
#10MeSH descriptor: [Iliac Artery] explode all trees and with qualifiers: [Surgery - SU]54
#11MeSH descriptor: [Tibial Arteries] explode all trees and with qualifiers: [Surgery - SU]7
#12(atherosclero* or arteriosclero* or PVD or PAOD or PAD) 17195
#13(arter*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*) 4872
#14(vascular) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*) 1378
#15(vein*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*) 713
#16(veno*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*) 976
#17(peripher*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*) 1358
#18(isch* or CLI) 16827
#19dysvascular* 14
#20leg near/4 (obstruct* or occlus* or steno* or block* or obliter* or thrombo*) 406
#21limb near/4 (obstruct* or occlus* or steno* or block* or obliter* or thrombo*) 362
#22(lower near/3 extrem*) near/4 (obstruct* or occlus* or steno* or block* or obliter* or thrombo*) 218
#23(iliac or femoral or popliteal or femoro* or fempop* or crural or ilio*) near/3 (obstruct* or occlus* or thrombo*) 293
#24#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 37927
#25MeSH descriptor: [Thrombolytic Therapy] explode all trees1556
#26MeSH descriptor: [Fibrinolytic Agents] explode all trees1758
#27MeSH descriptor: [Plasminogen Activators] explode all trees2142
#28urokinase or streptokinase or streptase or tenecteplase:ti,ab,kw  (Word variations have been searched)1885
#29reteplase or alteplase:ti,ab,kw  (Word variations have been searched)413
#30anistreplase or prourokinase or retavase or rapilysin:ti,ab,kw  (Word variations have been searched)206
#31t-PA or tPA:ti,ab,kw  (Word variations have been searched)954
#32r-PA or rPA:ti,ab,kw  (Word variations have been searched)53
#33lysis or lytic or thromboly*:ti,ab,kw  (Word variations have been searched)3922
#34plasminogen near/2 activator:ti,ab,kw  (Word variations have been searched)2873
#35clot near/3 (bust* or break* or remov*):ti,ab,kw  (Word variations have been searched)54
#36#25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 7254
#37#24 and #36 in Trials2243

What's new

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

DateEventDescription
10 April 2013New search has been performedSearches were rerun. No new studies included. One additional study excluded.
10 April 2013New citation required but conclusions have not changedSearches were rerun. No new studies included. One additional study excluded. Minor copy edits made. Conclusions not changed.

History

Protocol first published: Issue 2, 1998
Review first published: Issue 4, 2000

DateEventDescription
11 February 2009New search has been performed

Dates of last searches updated. No new trials found.

New CENTRAL search strategy.

31 October 2008AmendedConverted to new review format.
21 February 2007New search has been performedNew Plain Language Summary added. Copy edits made throughout text and in analysis graph labels. Acknowledgements and search strategy for CENTRAL updated. Dates of last searches updated. No new trials found; conclusions remain unchanged.
23 February 2006New search has been performedNo new trials found during most recent literature search. Review updated with minor style guide changes.
17 November 2004AmendedReview updated by minor change to Conflict of interest section to clarify about payment of consultancy fees.
23 August 2004AmendedNo new trials found. Review updated by minor changes to format to comply with Cochrane style guide.
21 May 2002New search has been performedUpdated review includes extra information from follow up trial references.

Contributions of authors

DCB identified all possible trials; selected trials for inclusion; assessed quality of trials and extracted data.

DK selected trials for inclusion; assessed quality of trials and extracted data.

IR selected trials for inclusion; assessed quality of trials and extracted data.

Declarations of interest

We certify that any past or present affiliations with, or involvement in, any organisation or entity with a direct financial interest in the subject matter or materials discussed in the review (e.g. employment, consultancies, stock ownership, honoraria, expert testimony) are listed below:

Consultancy fee was paid to Mr David Berridge, received in approximately 1990, from Boehringer Ingelheim for advice about clinical use/efficacy/safety/research implications of recombinant tissue plasminogen activator.

There is no ongoing affiliation with any relevant commercial company.

Sources of support

Internal sources

  • St James's University NHS Hospital, UK.

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 first of three reviews concerning different aspects of thrombolysis, all of which are covered by the generic protocol 'Surgery versus thrombolysis for acute limb ischaemia', unique ID 031499080512564323.

The second review is 'Infusion techniques for peripheral arterial thrombolysis'. The third review is 'Fibrinolytic agents for peripheral arterial occlusion'.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Nilsson 1992

Methods

Study design: RCT.

Method of randomisation: Not stated.

Concealment of allocation: Unblinded.

Intention to treat: No.

Exclusions post randomisation: None.

Lost to follow up: 1.

Participants

Country: Sweden.

No. of pats: 20.

Gender: 13 men, 7 women.

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

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

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

Interventions

1) Surgery: balloon thromboembolectomy (n = 9)

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

OutcomesFollow up at 30 days:
revascularisation; failure of lysis; amputation; ankle/brachial pressure index.
NotesNo use of Fontaine or Rutherford classification of severity of ischaemia.
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Ouriel 1994

Methods

Study design: RCT.

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

Concealment of allocation: Unblinded.

Intention to treat: Yes.

Exclusions post randomisation: Not stated.

Lost to follow up: Not stated.

Participants

Country: USA.

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

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

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

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

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

Interventions

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

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

OutcomesFollow up at 12 months:
limb salvage; amputation; patency rate; duration of hospitalisation; event free survival; time to reperfusion; bleeding complications; death.
NotesUsed Rutherford classification of critical ischaemia.
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Ouriel 1996

Methods

Study design: RCT.

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

Concealment of allocation: Unblinded.

Intention to treat: Yes.

Exclusions post randomisation: 4

Lost to follow up: Not stated.

Participants

Country: USA and Canada.

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

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

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

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

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

Interventions

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

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

Outcomes

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

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

NotesOrder of severity of interventions were compared from the initial predicted intervention to the actual intervention ultimately required by the time of initial hospital discharge.
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Ouriel 1998a

Methods

Study design: RCT.

Method of randomisation: Concealed telephone randomisation.

Concealment of allocation: Unblinded.

Intention to treat: Yes.

Exclusions post randomisation: 4

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

Participants

Country: USA and Northern Europe, 113 centres.

No. of pats: 548 recruited.

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

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

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

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

Interventions

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

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

OutcomesFollow up at 6 and 12 months:
Amputation-free survival at 6 and 12 months; survival free of open surgical procedures at 6 months (lysis group); ankle/brachial pressure index; degree of clot lysis; rates of adverse effects of treatment, including haemorrhagic complications.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

STILE 1994

  1. a

    APTT: activated partial thromboplastin time
    BP: blood pressure
    RCT: randomised controlled trial
    rt-PA: recombinant tissue plasminogen activator
    TIA: trans-ischaemic attack

Methods

Study design: RCT.

Method of randomisation: Concealed telephone randomisation.

Concealment of allocation: Unblinded.

Intention to treat: Yes and per protocol.

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

Lost to follow up: 4.

Participants

Country: USA.

No. of pats: 392.

Gender: 268 men, 124 women.

Mean age: 62.5 years.

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

Exclusion criteria: Infected peripheral arterial bypass grafts, previous enrolment in this trial, acute embolic occlusion, active internal bleeding, history of any cerebrovascular accident or intracranial bleeding, history of any TIA, intracranial or intraspinal surgery or trauma within past 2 months, any central nervous system neoplasm or aneurysm, known severe bleeding diathesis, severe uncontrolled hypertension (systolic BO greater than 180 mmHg and diastolic BP greater than 110 mm Hg), known or suspected pregnancy or child bearing potential, eye surgery within past 3 months, inability to undergo surgical procedure e.g. contraindication to general anaesthetic, severe cardiac disease, recent puncture of non compressible vessel, participation in another research protocol within the last 30 days.

Other criteria which the investigators had to exercise good clinical judgment included recent vascular surgery, major non-vascular surgery within 10 days, significant liver dysfunction, history of internal bleeding or other significant bleeding within past 10 days, high likelihood of left heart thrombus, acute pericarditis or subacute bacterial endocarditis, trauma within past 10 days, asymptomatic cerebrovascular disease, diabetic or haemorrhage retinopathy, haemostatic defects, low platelet count, septic thrombophlebitis or occluded AV cannula at a seriously infected site, any other condition in which bleeding is a significant hazard, severe ischaemia which requires immediate surgical intervention.

Interventions

1) Surgical revascularisation including primary amputation.

2) Thrombolysis - choice of lytic agent used chosen by investigators, either rt-PA 0.05 mg/kg/hr for up to 12 hours (max dose 200 mg) or urokinase 250,000 IU bolus followed by 4000 IU/min for 4 hours, then 2000 IU/min for up to 36 hours.

In addition, participants in the thrombolysis group received 5000 IU heparin as an intravenous bolus at the time of thrombolysis followed by 1000 U/hour titrated to maintain the APTT between 1.5 to 2.0 times the control, plus 325 mg aspirin at the time of randomisation and daily thereafter.

OutcomesFollow up at 6 months: Composite Clinical Outcome; ongoing or recurrent ischaemia; death or major amputation; life-threatening haemorrhage; perioperative complications; renal failure requiring dialysis; serious anaesthesia related complications; vascular complications; post-interventional wound complications; clinical improvement and reduction in surgery; patency and perfusion status; duration of ischaemia; length of hospitalisation.
NotesFor further details of 'Composite Clinical Outcome' see original paper
NOTE: Two further reports concerning 12 month data on native arteries and grafts from this study have been published as Weaver 1996 and Comerota 1996. These are discussed in the main body of the text in conjunction with the original paper.
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Patel 1999Markov analysis of cost-effectiveness based on TOPAS database, but no actual prospective economic data collection was performed as part of the TOPAS trial itself.
Tiek 2009Non randomised controlled study.