Primary prophylaxis for venous thromboembolism in people undergoing major amputation of the lower extremity

  • Review
  • Intervention

Authors


Abstract

Background

Patients undergoing major amputation of the lower limb are at increased risk of venous thromboembolism (VTE). Risk factors for VTE in amputees include advanced age, sedentary lifestyle, longstanding arterial disease and an identifiable hypercoagulable condition. Evidence suggests that pharmacological prophylaxis (for example heparin, factor Xa inhibitors, vitamin K antagonists, direct thrombin inhibitors, antiplatelets) is effective in preventing deep vein thrombosis (DVT) but it is associated with an increased risk of bleeding. Mechanical prophylaxis (for example antiembolism stockings, intermittent pneumatic compression and foot impulse devices), on the other hand, is non-invasive and has no side effects. However, it is not always appropriate in patients with contraindications such as peripheral arterial disease (PAD), arteriosclerosis or bilateral lower limb amputations. It is important to determine the most effective thromboprophylaxis and whether this is one treatment alone or in combination with another. To date, no systematic review has been conducted examining the effectiveness of thromboprophylaxis in preventing VTE in people undergoing amputation.

Objectives

To determine the effectiveness of thromboprophylaxis in preventing VTE in people undergoing major amputation of the lower extremity.

Search methods

The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2013) and CENTRAL (2013, Issue 4). Clinical trials databases were searched (May 2013). No date or language restrictions were applied. Non-English trials were translated where required and reference lists of identified studies were handsearched.

Selection criteria

Randomised controlled trials and quasi-randomised controlled trials in which people undergoing a major unilateral or bilateral amputation (for example hip disarticulation, transfemoral, knee disarticulation and transtibial) of the lower extremity were allocated to different types or regimens of thromboprophylaxis (including pharmacological or mechanical prophylaxis) or placebo.

Data collection and analysis

Selection of studies, data extraction and risk of bias were completed independently by two review authors. Any disagreements were resolved by discussion. Meta-analysis could not be completed as the two included studies compared different treatments and therefore the data could not be pooled.

Main results

Two studies with a combined total of 288 participants met the inclusion criteria for this review. One study compared low molecular weight heparin with unfractionated heparin and found no difference between the treatments in the prevention of DVT (odds ratio (OR) 1.23, 95% confidence interval (CI) 0.28 to 5.35). No bleeding events or deaths occurred. This study was open label and therefore at a high risk of performance bias. Additionally, the method of randomisation was not reported and therefore the risk of selection bias was unclear. In the second study heparin did not significantly improve prevention of pulmonary embolism (OR 1.02, 95% CI 0.44 to 2.37) when compared to placebo. Furthermore, when the level of amputation was considered, the incidence of pulmonary embolism was similar between the two treatment groups: above knee amputation (OR 0.79, 95% CI 0.31 to 1.97) and below knee amputation (OR 1.53, 95% CI 0.09 to 26.43). Ten participants died during the study; five underwent a post-mortem and three were found to have had a recent pulmonary embolism, all of whom had been on placebo. Bleeding events were reported in less than 10% of participants in both treatment groups but specific data were not presented. This study did not report the methods used to conceal allocation of treatment and therefore it was unclear if selection bias occurred. However, this study appeared to be free from all other sources of bias. No study looked at mechanical prophylaxis.

Authors' conclusions

As only two studies were included in this review, each comparing different interventions, there is insufficient evidence to make any conclusions regarding the most effective thromboprophylaxis regimen in patients undergoing lower limb amputation. Further large-scale studies that are of good quality are required.

Résumé scientifique

La prophylaxie primaire de la thromboembolie veineuse chez les personnes subissant une amputation majeure de l'extrémité inférieure

Contexte

Les patients subissant une amputation majeure du membre inférieur courent un risque accru de thromboembolie veineuse (TEV). Les facteurs de risque de TEV chez des amputés incluent un âge avancé, la sédentarité, les maladies artérielles de longue durée et un trouble d'hypercoagulabilité identifiable. Les preuves suggèrent que la prophylaxie pharmacologique (par exemple l'héparine, les inhibiteurs du facteur Xa, les antagonistes de la vitamine K, les inhibiteurs directs de la thrombine, les antiplaquettaires) est efficace pour prévenir la thrombose veineuse profonde (TVP), mais elle est associée à un risque accru de saignement. La prophylaxie mécanique (par exemple, les bas anti-emboliques, la compression pneumatique intermittente et les dispositifs de stimulation fonctionnelle du pied), d'autre part, est non invasive et n'a pas d'effets secondaires. Cependant, elle n'est pas toujours appropriée chez les patients présentant des contre-indications telles que la maladie artérielle périphérique (MAP), l'artériosclérose ou une amputation bilatérale des membres inférieurs. Il est important de déterminer la thromboprophylaxie la plus efficace et s'il s'agit d'un traitement seul ou en association avec un autre. À ce jour, aucune revue systématique n'a été menée pour examiner l'efficacité de la thromboprophylaxie dans la prévention de la TEV chez les personnes subissant une amputation.

Objectifs

Déterminer l'efficacité de la thromboprophylaxie dans la prévention de la TEV chez les personnes subissant une amputation majeure de l'extrémité inférieure.

Stratégie de recherche documentaire

Le coordinateur de recherche d'études du groupe Cochrane sur les maladies vasculaires périphériques a effectué des recherches dans le registre spécialisé (dernière recherche en mai 2013) et dans CENTRAL (2013, numéro 4). Diverses bases de données d'essais cliniques ont également été consultées (mai 2013). Aucune restriction concernant la langue ou la date n'a été appliquée. Les études publiées dans d'autres langues que l'anglais ont été traduites au besoin et les références bibliographiques des études identifiées ont été examinées manuellement.

Critères de sélection

Des essais contrôlés randomisés et quasi-randomisés dans lesquels les personnes subissant une amputation majeure unilatérale ou bilatérale de l'extrémité inférieure (par exemple une désarticulation de la hanche ou du genou, ou une amputation transfémorale ou transtibiale) ont été assignées à différents types de thromboprophylaxie (y compris la prophylaxie mécanique ou pharmacologique) ou à un placebo.

Recueil et analyse des données

La sélection des études, l'extraction des données et l'évaluation du risque de biais ont été effectuées de manière indépendante par deux auteurs de la revue. Les désaccords éventuels ont été résolus par la discussion. Une méta-analyse n'a pas pu être conduite puisque les deux études incluses comparaient des traitements différents et par conséquent, les données n'ont pas pu être combinées.

Résultats principaux

Deux études portant sur un total combiné de 288 participants remplissaient les critères d'inclusion pour cette revue. La première a comparé l'héparine de bas poids moléculaire avec l'héparine non fractionnée et n'a trouvé aucune différence entre ces deux traitements dans la prévention de la TVP (rapport des cotes (RC) 1,23, intervalle de confiance (IC) à 95% 0,28 à 5,35). Aucun événement hémorragique ou décès n'est survenu. Cette étude était ouverte et présentait donc un risque élevé de biais de performance. En outre, la méthode de randomisation n'était pas rapportée et par conséquent, le risque de biais de sélection n'était pas clair. Dans la deuxième étude, l'héparine n'a pas apporté d'amélioration significative dans la prévention de l'embolie pulmonaire (RC 1,02, IC à 95% 0,44 à 2,37) par rapport à un placebo. De plus, lorsque le niveau de l'amputation a été pris en compte, l'incidence de l'embolie pulmonaire était similaire entre les deux groupes de traitement: amputation au-dessus du genou (RC 0,79, IC à 95% 0,31 à 1,97) et en-dessous du genou (RC 1,53, IC à 95% 0,09 à 26,43). Dix participants sont décédés pendant l'étude; une autopsie a été pratiquée sur cinq d'entre eux et il a été découvert que trois avaient récemment été victimes d'une embolie pulmonaire, tous ayant été sous placebo. Des événements hémorragiques ont été rapportés chez moins de 10% des participants dans les deux groupes de traitement, mais les données exactes n'étaient pas présentées. Cette étude ne rapportait pas les méthodes utilisées pour l'assignation secrète du traitement et par conséquent, il était difficile de savoir si un biais de sélection était présent. Cependant, cette étude semblait être exempte de toute autre source de biais. Aucune étude n'a examiné la prophylaxie mécanique.

Conclusions des auteurs

Puisque deux études seulement ont été incluses dans cette revue, et chacune d'entre elles comparait des interventions différentes, il n'existe pas suffisamment de preuves pour tirer des conclusions quant à la thromboprophylaxie la plus efficace chez les patients subissant une amputation du membre inférieur. D'autres études à grande échelle et de bonne qualité sont nécessaires.

Plain language summary

Venous blood clot prevention in people undergoing lower limb amputation

Amputation of the leg is most often performed to remove dead tissue (gangrene), painful ulcers, tumours, or tissue with an inadequate blood supply. One of the most common causes of an inadequate blood supply is a narrowing of the arteries of the legs, which accounts for approximately 70% of amputations. In patients with this condition, blood clots are more likely to cause problems such as venous thromboembolism (VTE). This comprises two conditions, a blood clot in the legs (deep vein thrombosis (DVT)) or a blood clot in the arteries of the lungs (pulmonary embolism (PE)). The risk of these events occurring is higher in people undergoing amputations. There are two forms of preventive measures for VTE, drugs or compression devices. Drugs are proven to be effective in preventing VTE but are also associated with adverse side effects. Compression stockings or devices do not cause side effects but are not suitable for everyone. Current guidelines recommend that any person undergoing an amputation of the lower limb should be offered drugs to prevent a blood clot. However, in people with amputations it is not clear which method is best. This review aimed to establish the best method.

After searching for relevant studies, we found two studies with a combined total of 288 participants to be included in this review of evidence. One study compared two forms of the anticoagulant heparin. Low molecular weight heparin offered no significant improvement over unfractionated heparin in the prevention of DVT. Furthermore neither drug caused bleeding. However, in this study both the participants and study personnel were aware of which treatment was being administered. This may have biased the results. It is unclear if other bias was introduced in the study because the process of randomly allocating treatment was not adequately described. The second study concluded that heparin was not more effective in preventing a PE than placebo whether the amputation was above or below the knee. Bleeding occurred in less than 10% of each treatment group but the study authors did not report specific numbers and therefore this could not be analysed. This study did not report the methods used to conceal how treatment was allocated but it was judged to be free from other sources of bias.

This review found that there are too few trials to determine the most effective strategy in preventing VTE in people undergoing amputation of the lower limb. No study looked at mechanical forms of preventing VTE, such as compression devices, and therefore it is not possible to make any conclusions about these. Further good quality and large-scale studies are required.

Résumé simplifié

Prévention de caillots de sang veineux chez les personnes subissant une amputation du membre inférieur

Une amputation de la jambe est le plus souvent pratiquée pour retirer des tissus morts (gangrène), des ulcères douloureux, des tumeurs, ou des tissus avec un apport sanguin insuffisant. L'une des causes les plus courantes d'un apport sanguin insuffisant est un rétrécissement des artères des jambes, ce qui représente environ 70% des amputations. Chez les patients atteints de cette condition, les caillots de sang sont plus susceptibles d'entraîner des problèmes tels que la thromboembolie veineuse (TEV). Cette appellation correspond à deux pathologies, un caillot de sang dans les jambes (thrombose veineuse profonde (TVP)) ou un caillot sanguin dans les artères des poumons (embolie pulmonaire (EP)). Le risque d'occurrence de ces événements est plus élevé chez les personnes subissant des amputations. Il existe deux types de mesures préventives pour la TEV, les médicaments ou les dispositifs de compression. Les médicaments ont démontré leur efficacité dans la prévention de la TEV, mais ils sont également associés à des effets secondaires indésirables. Les bas de contention ou les autres dispositifs de compression ne provoquent pas d'effets secondaires, mais ne conviennent pas à tout le monde. Les recommandations actuelles stipulent de donner à toute personne subissant une amputation des membres inférieurs des médicaments pour prévenir un caillot sanguin. Cependant, il n'est pas clair quelle méthode est la meilleure chez les personnes subissant une amputation. Cette revue visait à le déterminer.

Après avoir recherché des études pertinentes, nous avons trouvé deux études avec un total combiné de 288 participants pour être incluses dans cette revue de preuves. La première étude comparait deux formes de l'anticoagulant héparine. L'héparine de bas poids moléculaire n'a apporté aucune amélioration significative par rapport à l'héparine non fractionnée dans la prévention de la TVP. Par ailleurs, aucun des deux médicaments n'a provoqué de saignement. Cependant, dans cette étude les participants ainsi que les organisateurs savaient quel traitement était administré. Cela peut avoir faussé les résultats. Il n'est pas clair si d'autres biais étaient présents dans cette étude, car le processus d'attribution aléatoire des traitements n'était pas correctement décrit. La deuxième étude a conclu que l'héparine n'était pas plus efficace que le placebo pour prévenir une EP, que l'amputation se fasse au-dessus ou en-dessous du genou. Des saignements sont survenus dans moins de 10% des cas dans chaque groupe de traitement, mais les auteurs de l'étude ne rapportant pas de chiffres exacts, ces données n'ont pu être analysées. Cette étude ne rapportait pas les méthodes utilisées pour masquer la manière dont le traitement était assigné mais elle a été jugée exempte d'autres sources de biais.

Cette revue a conclu qu'il existe trop peu d'essais pour déterminer la stratégie la plus efficace pour la prévention de la TEV chez les personnes subissant une amputation du membre inférieur. Aucune étude n'examinait les formes mécaniques de prévention de la TEV, telles que les dispositifs de compression, et par conséquent, aucune conclusion n'a pu être formulée à ce sujet. Des études supplémentaires de bonne qualité et à grande échelle sont nécessaires.

Notes de traduction

Traduit par: French Cochrane Centre 14th January, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Background

Description of the condition

Lower extremity amputation is performed to remove ischaemic (tissue with a restricted blood supply), infected or necrotic tissue, or in tumour involvement of the surrounding bone or tissue. Dysvascularities (loss of or defective blood supply in a limb), including those related to peripheral vascular disease (PVD) and diabetes mellitus, account for 72% of lower limb amputations in the UK (NASDAB 2009). Trauma, infection, malignancy and neurological disorders account for the remainder of cases (Dillingham 2002; Heikkinen 2007; Ziegler-Graham 2008). PVD includes arterial, venous and lymphatic disease. The prevalence of PVD in the general population is 12% to 14%, and increases to 20% in those aged over 70 years (Shammas 2007). Furthermore, the prevalence is higher still in people with diabetes, an estimated 29% (American Diabetes Association 2003). The observed increase in life expectancy in the UK (Office for National Statistics), coupled with the 50% increase in the incidence of diabetes since 1997 (Kanavos 2012), means that the prevalence of PVD is likely to rise. As a consequence, more people are likely to require amputation of the lower extremity.

People undergoing major lower extremity amputation are at high risk of venous thromboembolism (VTE) (Burke 2000; Harper 1973; Huang 2005; Libertiny 1999; Yeager 1995). Major lower limb amputations are classed as hip disarticulation, transfemoral (above knee), knee disarticulation and transtibial (below knee). Studies have shown the incidence of VTE in people undergoing major lower limb amputation to be between 9.4% (Bandeira 2008) and 13.2% (Struijk-Mulder 2010a). Risk factors for VTE that are common to people undergoing amputations are advanced age, sedentary lifestyle, longstanding arterial disease and an identifiable hypercoagulable condition (Yeager 1995). While surgery itself is an important and established risk for VTE, it is thought that the slower blood flow proximal to the ligated veins combined with the endothelial trauma to the veins during amputation predisposes amputees to a higher risk of deep vein thrombosis (DVT) than other surgical patients (Lastória 2006).

Description of the intervention

There are two types of thromboprophylaxis, pharmacological and mechanical. The type of prophylaxis administered depends upon individual patient risk, amputation level and expected level of activity following amputation. Both pharmacological and mechanical prophylaxis have been shown to reduce the incidence of VTE in post-surgical patients. However, pharmacological prophylaxis is associated with adverse events such as heparin-induced thrombocytopenia (HIT) (a relative decrease of platelets in the blood) and bleeding. Clinicians have to consider the risk of VTE against the risk of adverse events. Unlike pharmacological prophylaxis, methods of mechanical prophylaxis are not associated with increased risk of bleeding. However, mechanical prophylaxis is not appropriate for people with peripheral arterial disease, arteriosclerosis, gangrene or double lower limb amputation. Furthermore, applying mechanical prophylaxis to just one leg may not prevent DVT in the proximal veins on the side undergoing amputation.

How the intervention might work

Pharmacological prophylaxis

There are several pharmacological agents for the prevention of VTE.

1. Heparins

Unfractionated heparin (UFH) acts as an anticoagulant, thus preventing the formation of clots or extensions of existing clots within the blood. It binds to the enzyme inhibitor antithrombin, which inactivates the effect of thrombin and other coagulation enzymes involved in blood clotting (X, IX, XI and XII) (Chuang 2001). UFH can be administered intravenously or by subcutaneous injection (UK National Clinical Guidelines 2010). UFH has a short half-life of approximately one hour and therefore requires frequent or continuous infusions (Eikelboom 2002). However, its lower weight derivative (low molecular weight heparin (LMWH)) has a half-life of four to five hours, allowing once daily dosing (Weitz 2004). Heparin can be used as a prophylactic measure or to treat VTE. Heparin can cause serious side effects, including heparin-induced thrombocytopenia (HIT), defined as a decrease in platelet count during or following exposure to heparin (Warkentin 2004). Evidence has shown that approximately 1% to 5% of people on heparin will develop HIT (Baglin 1997; Kelton 2002). HIT is a serious and potentially life-threatening condition (Franchini 2005).

2. Factor Xa inhibitor

Fondaparinux also binds to antithrombin but, unlike heparin, it does not inhibit thrombin. Instead, the binding of fondaparinux to antithrombin selectively inactivates factor Xa thus inhibiting coagulation (Bauer 2002). It has a longer half-life than heparin, allowing it to be administered once daily as a subcutaneous injection (UK National Clinical Guidelines 2010). Fondaparinux has been shown to be as effective and as safe as adjusted dose, intravenous administration of UFH in the initial treatment of pulmonary embolism (PE) (Matisse 2003). Furthermore, as fondaparinux does not interact with platelets, there is no risk of HIT (Bauer 2001). Fondaparinux is more expensive than heparin, which may limit its use. Another factor Xa inhibitor, rivaroxaban, has been approved in Canada and Europe for the prevention of VTE in people who have undergone elective total hip or knee replacement. The National Institute for Health and Clinical Excellence published guidelines reviewing evidence from four randomised controlled trials involving over 12,000 people undergoing total hip or knee replacement (NICE 2009). Results showed that although rivaroxaban is at least as effective as LMWH in the prevention of VTE, it is associated with a higher rate of major bleeding.

3. Vitamin K antagonists

Warfarin is a synthetic derivative of coumarin, a chemical found naturally in many plants. It acts as a vitamin K antagonist, which, in turn, reduces the amount of active clotting factors thereby producing a state of anticoagulation (Holford 1986). The effect of warfarin is not immediate. It is administered at a variable dose that is adjusted until it reaches a therapeutic level defined by an international normalised ratio (INR) of 2.5 (Ansell 2008). The response to warfarin varies according to several factors including, age, genetic status, medications, diet, underlying medical conditions and smoking status (UK National Clinical Guidelines 2010). Due to the time taken to achieve a therapeutic level sufficient to protect against thromboembolic events, people undergoing surgery stop warfarin upon admission to hospital and heparin, which provides immediate anticoagulation, is given (UK National Clinical Guidelines 2010). Bleeding is the primary adverse event associated with warfarin. Although the effects of warfarin can be reversed through discontinuation of the drug, or administration of vitamin K or prothrombin concentrate, the reversal is permanent and often difficult to achieve (UK National Clinical Guidelines 2010).

4. Direct thrombin inhibitors

Direct thrombin inhibitors (DTIs) act as anticoagulants by directly inhibiting the enzyme thrombin and thus delaying blood clotting. The DTI dabigatran has been approved in Canada and Europe for thromboprophylaxis for hip and knee replacement, while other DTIs are undergoing clinical development. Unlike warfarin, DTIs are immediately effective and do not require dose adjustment and close monitoring (UK National Clinical Guidelines 2010). However, the anticoagulation effect of DTIs is non-reversible.

5. Antiplatelets

Aspirin has an antiplatelet effect by inhibiting the production of thromboxane. Guidelines have recommended aspirin as primary prophylaxis for the prevention of VTE following orthopaedic surgery (Falck-Ytter 2012). Prolonged use of aspirin has been shown to increase the risk of gastrointestinal bleeding and stomach ulcers, particularly when taken with warfarin (Sørensen 2000).

Mechanical prophylaxis

Mechanical devices work to reduce venous stasis in the leg, a known risk factor for VTE (Morris 2004). They are non-invasive and, unlike pharmacological prophylaxis, there is no risk of bleeding. Depending on the estimated risk of VTE, mechanical devices can be used alone or in combination with pharmacological prophylaxis (UK National Clinical Guidelines 2010). Methods include antiembolism stockings (AES), intermittent pneumatic compression devices (IPCD) and foot impulse devices (FID), also known as foot pumps.

1. Antiembolism stockings (AESs)

AESs exert graded circumferential pressure from the distal to the proximal regions of the leg. They have two potential actions in preventing DVT in immobile people. First, exerting graduated compression increases blood flow velocity, which promotes venous return; and second, preventing passive venous distension is thought to prevent subendothelial tears and the activation of clotting factors (UK National Clinical Guidelines 2010). AESs are contraindicated in people with peripheral arterial disease and arteriosclerosis.

2. Intermittent pneumatic compression devices (IPCDs)

IPCDs comprise inflatable cuffs placed around the foot, calf or thigh that are intermittently inflated, powered by a pneumatic pump. The inflation and deflation process stimulates the calf muscle pump, thus forcing blood in the deep veins up towards the heart. This increases the velocity of blood flow in the deep veins of the leg thereby reducing venous stasis and hypertension (Goucke 1989). Calf compression with an IPCD has also been shown to enhance fibrinolysis, a process that augments thrombus breakdown and prevents clot formation (Storti 1996).

3. Foot impulse devices (FIDs)

FIDs (or foot pumps) act by creating the effect of walking in immobilised people. During ambulation, the muscle pump in the foot forces blood in the deep veins upwards towards the heart. This action increases venous outflow in the deep veins, thereby reducing stasis and venous hypertension and preventing the formation of blood clots in the legs (Gardner 1983). FIDs recreate this physiological process through artificially stimulating the foot pump, thereby mimicking the effect of walking (UK National Clinical Guidelines 2010).

Why it is important to do this review

Evidence from observational studies in people undergoing major lower extremity amputation supports the use of pharmacological thromboprophylaxis (Burke 2000; Harper 1973; Hill 2010; Huang 2005; Lastória 2006; Yeager 1995). Indeed, one study reported that DVT occurred in 50% of people following major lower extremity amputation without prophylaxis (Harper 1973). In one randomised trial comparing LMWH and UFH for amputations, the incidence of DVT was similar in each group at about 10% (Lastória 2006). Nevertheless, some evidence suggests that despite the use of pharmacological thromboprophylaxis (with LMWH), the rate of VTE in people undergoing amputation remains high (Struijk-Mulder 2010a). Mechanical prophylaxis, including IPCDs and AESs, has been proposed as a useful addition to pharmacological prophylaxis (Struijk-Mulder 2010b) but this is not always appropriate in amputees with contraindications.

The Scottish Intercollegiate Guidelines Network recommend thromboprophylaxis in all people undergoing all major lower extremity amputations (SIGN 2010). With conflicting reports regarding the efficacy of thromboprophylaxis, it is imperative to determine the most effective. To date, no systematic review has been conducted examining the effectiveness of thromboprophylaxis in preventing VTE in people undergoing amputation. 

Objectives

To determine the effectiveness of thromboprophylaxis in preventing VTE in people undergoing major amputation of the lower extremity.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials and quasi-randomised controlled trials in which people undergoing an amputation of the lower extremity were allocated to receive different types of thromboprophylaxis. We included published studies and studies in progress if preliminary results were available. Non-English studies were also eligible for inclusion in the review.

Types of participants

People undergoing major unilateral or bilateral amputation (hip disarticulation, transfemoral (above knee), knee disarticulation, ankle disarticulation and transtibial (below knee) of the lower extremity). Patients undergoing minor amputations of the toes or a portion of the foot were excluded.

Types of interventions

  • Pharmacological prophylaxis (LMWH, UFH, factor Xa inhibitors, vitamin K antagonists, DTIs, antiplatelets)

  • Mechanical prophylaxis (AES, IPCD, FID) (for unilateral amputees only)

Comparisons included:

  1. one pharmacological prophylaxis versus another (e.g. LMWH versus UFH);

  2. one mechanical prophylaxis versus another (e.g. AES versus FID);

  3. pharmacological prophylaxis versus mechanical prophylaxis;

  4. pharmacological plus mechanical prophylaxis versus mechanical prophylaxis alone;

  5. prophylaxis (pharmacological or mechanical, or both) versus placebo.

Types of outcome measures

Primary outcomes
  • Total VTE (non-fatal and fatal)

  • Symptomatic or asymptomatic non-fatal VTE (DVT or PE) confirmed by diagnostics tests, including helical computed tomography (CT), CT angiography and ventilation-perfusion lung scintigraphy for diagnosis of PE; and complete compression ultrasonography and impedance plethysmography (test in which air is used to determine circulatory capacity) for diagnosis of DVT

Secondary outcomes
  • All-cause mortality.

  • Adverse events (HIT).

  • Bleeding, as defined by the Bleeding Academic Research Consortium Definition for Bleeding (Mehran 2011):

  1. type 0 - no bleeding;

  2. type 1 - no actionable bleeding;

  3. type 2 - overt bleeding requiring either non-surgical intervention or hospitalisation, or prompting evaluation;

  4. type 3 - overt bleeding with a drop in haemoglobin (Hb). Subdivided into 3a (Hb drop 3 to 5 g/dL, 3b (Hb drop > 5 g/dL or 3c (intracranial haemorrhage);

  5. type 5 - fatal bleeding.

Search methods for identification of studies

Electronic searches

The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched May 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 4), 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 and 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).

The following trial databases were searched in May 2013 by the TSC for details of ongoing and unpublished studies using the terms (amputation and (leg or lower)):

Searching other resources

Non-English trials were translated where required and reference lists of identified studies were searched.

Data collection and analysis

Selection of studies

One review author (LR) used the selection criteria to identify trials for inclusion and the second review author (AR) independently confirmed this selection. Any disagreements were resolved by discussion.

Data extraction and management

Two review authors (LR, AR) independently extracted the data. Information about the trial design, type of amputation, baseline characteristics of participants and type of prophylaxis was recorded. Non-fatal and fatal VTE data were recorded as the primary outcome measures. Information on bleeding and deaths was collected in accordance with the secondary outcome measures. Authors of the included studies were contacted if further information or clarification was required. Any disagreements in data extraction and management were resolved by discussion.

Assessment of risk of bias in included studies

Two review authors (LR, AR) independently used the Cochrane Collaboration's 'Risk of bias' tool for assessing risk of bias for each of the included studies (Higgins 2011). The tool provides a protocol for judgements on sequence generation, allocation methods, blinding, incomplete outcome data, selective outcome reporting and any other relevant biases. Any disagreements were resolved by discussion.

Measures of treatment effect

Analysis was based on intention-to-treat data from the individual clinical trials. As the primary and secondary outcomes were all binary measures, odds ratios (ORs) were computed using a random-effects model and 95% confidence intervals (CI) of the effect sizes were calculated.

Unit of analysis issues

The unit of analysis within each trial was the individual patient.

Dealing with missing data

Information about dropouts, withdrawals and other missing data was sought and, if not reported, study authors were contacted for this information.

Assessment of heterogeneity

The inclusion of studies on a wide range of medical treatments is likely to result in a high degree of heterogeneity. We planned to assess the heterogeneity between pooled studies by using the Chi2 test regarding the characteristics and quality of the included studies. We planned to use the I2 statistic to measure the degree of inconsistency between studies, with results of 50% representing moderate to substantial heterogeneity (Deeks 2011). However, only two studies were included in this review. The studies tested different drugs and it was not possible to pool the data. Therefore, heterogeneity between studies was not assessed.

Assessment of reporting biases

We planned to assess reporting biases such as publication bias by funnel plots. There are many reasons for funnel plot asymmetry and we consulted the Cochrane Handbook for Systematic Reviews of Interventions (Sterne 2011) to aid the interpretation of the results. However, as only two studies were included in the review it was not possible to test for funnel plot asymmetry.

Data synthesis

The review authors independently extracted the data. One review author (LR) inputted the data into Review Manager (RevMan 2011) while the second review author (AR) cross-checked the data entry. Any discrepancies were resolved by consulting the source publication.

A random-effects model was used to analyse the data.

Subgroup analysis and investigation of heterogeneity

Where possible, we attempted to analyse clinically relevant subgroups based on type of prophylaxis and participant groupings. Subgroupings included:

  1. DVT or PE;

  2. indication for amputation;

  3. level of amputation (transfemoral, transtibial, exarticulation knee);

  4. history of VTE;

  5. diabetes;

  6. PVD (arterial, venous and lymphatic disease);

  7. smoking;

  8. body mass index (BMI);

  9. duration of prophylaxis.

Sensitivity analysis

We planned to conduct sensitivity analysis to examine the stability of the results in relation to the quality of the included studies. However, as only two studies were included in the review, it was not feasible to perform a sensitivity analysis.

Results

Description of studies

Results of the search

See: Figure 1

Figure 1.

Study flow diagram.

Included studies

See: Characteristics of included studies

One study was an open-label randomised controlled trial in which 75 patients undergoing elective or emergency lower limb amputation for critical limb ischaemia (CLI) were randomised to receive subcutaneous UFH (5000 IU twice daily) or 40 mg enoxaparin daily (Lastória 2006). Patients with a previous VTE or a contraindication to anticoagulant prophylaxis were excluded from the study. Prophylaxis began 12 hours before elective surgery or, in emergency cases, on the first day postoperatively. DVT was assessed by daily clinical examination and duplex ultrasound before surgery and again between five and eight days after surgery. DVT was diagnosed as an 'abnormal venous flow and evidence of intraluminal thrombi confirmed with compressive ultrasonography'. Of the 75 patients, 30 underwent an above-knee amputation while the remaining 45 had a below-knee amputation. Thirty-four patients were randomised to UFH and 41 were randomised to LMWH.

The second study (Williams 1978) was a randomised, double-blind trial in which 134 patients undergoing lower extremity amputation for the complications of ischaemic vascular disease were randomised to receive low dose heparin or placebo. Sixty-nine patients with an amputation (53 above knee and 16 below knee) received 10,000 USP units/ml of sodium heparin subcutaneously at a rate of 0.5 ml every 12 hours for two weeks or until discharge. Sixty-five patients (41 above knee and 24 below knee) received saline. Treatment was started approximately two hours before surgery. Lung perfusion scans were performed before surgery and then at weekly intervals for the duration of treatment. In patients with a new pulmonary perfusion defect, a pulmonary arteriography was performed and if that was unclear, an angiogram was done. PE was diagnosed if a new lobar, segmental or subsegmental perfusion defect appeared which was not attributable to an infiltrate, pleural effusion, vascular congestion or atelectasis appearing on the chest roentgenogram.

Excluded studies

See: Characteristics of excluded studies

Twelve studies were excluded (Atkins 1978; Covey 1975; Di Serio 1985; Haas 2005; Huttenen 1977; Kakkar 1978; Kakkar 2005; Kill 1979; Mantz 2011; Nicolaides 1972; Pachter 1977; Strand 1975), 11 of which were excluded as they did not include participants undergoing amputations (Atkins 1978; Covey 1975; Di Serio 1985; Haas 2005; Huttenen 1977; Kakkar 1978; Kakkar 2005; Kill 1979; Mantz 2011; Nicolaides 1972; Strand 1975). One study (Pachter 1977) was excluded as the authors did not state what the control treatment was. Additionally, the methods of diagnosing DVT and PE were not reported.

Risk of bias in included studies

See: Figure 2; Figure 3

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Although both studies were randomised, the study by Lastória 2006 did not provide any information on the method of randomisation used and therefore the risk of selection bias could not be assessed. The study by Williams 1978 used a random number table and therefore was at low risk of selection bias. In terms of concealing the allocation of treatment, the study by Lastória 2006 used serial number envelopes while the study by Williams 1978 did not report the methods used.

Blinding

Of the two studies, one was open label (Lastória 2006) and therefore at a high risk of performance bias. The remaining study (Williams 1978) blinded both study participants and personnel and was therefore at low risk of performance bias. Both studies blinded outcome assessors to the treatment and were deemed to be at low risk of detection bias.

Incomplete outcome data

Both studies accounted for all incomplete outcome data and were judged to be at low risk of attrition bias.

Selective reporting

Both studies reported data on all pre-specified primary and secondary outcomes and were therefore at low risk of reporting bias.

Other potential sources of bias

Both studies appeared to be free from other sources of bias.

Effects of interventions

Two studies (Lastória 2006; Williams 1978) were included in the review. One (Lastória 2006) compared UFH against LMWH and the second (Williams 1978) compared UFH with a placebo. No studies on mechanical prophylaxis, such as compression devices, were included in the review.

Unfractionated heparin (UFH) versus low molecular weight heparin (LMWH)

In the one study (Lastória 2006) comparing UFH with LMWH, four out of 34 participants randomised to UFH had a DVT compared to four out of 41 randomised to LMWH (OR 1.23, 95% CI 0.28 to 5.35). The study authors reported the number of participants with above and below knee amputations but did not present the results according to amputation type. The authors were contacted for this data but they did not respond to our communication. No bleeding events, adverse events or deaths occurred in either treatment group.

Heparin versus placebo

In the one study comparing UFH with a placebo (Williams 1978), the incidence of PE was similar in the heparin (14/69) and placebo (13/65) groups (OR 1.02, 95% CI 0.44 to 2.37). When analysed by type of amputation, heparin offered no significant improvement over placebo: above knee amputation OR of 0.79 (95% CI 0.31 to 1.97), below knee amputation OR of 1.53 (95% CI 0.09 to 26.43). The incidence of postoperative bleeding was less than 10% in both treatment groups, although the exact figures were not reported and the study authors did not respond to requests for these data. One participant randomised to placebo was removed prematurely from the study due to excessive bleeding. The study authors also reported that 10 participants died during the study. Of those 10, five underwent a post-mortem and three were found to have had a recent PE, all of whom were on placebo. There were no reports of other adverse events.

Discussion

Summary of main results

Only two studies were found which fulfilled the eligibility criteria for inclusion in this review. One study (Lastória 2006) compared the effectiveness of LWMH with UFH in the prevention of DVT up to eight days post-amputation. Neither drug was found to be significantly superior and no bleeding occurred in the study population. The second study (Williams 1978) was concerned with PE and found that heparin offered no significant improvement over a placebo regardless of the level of amputation. Neither study used mechanical prophylaxis in addition to pharmacological prophylaxis.

Overall completeness and applicability of evidence

At present, there is a severe lack of evidence concerning the effectiveness of pharmacological and mechanical prophylaxis in the prevention of VTE in patients with lower limb amputation. One study was open label and therefore at a high risk of performance bias. The two studies tested different drugs and outcomes and therefore the results could not be pooled in a meta-analysis. Only one study presented data according to the level of amputation. Neither study used mechanical prophylaxis in addition to the drugs administered. Furthermore, no study on mechanical prophylaxis was included in the review.

Quality of the evidence

The quality of reporting in the studies was generally good. The risk of selection bias was unclear as one study (Lastória 2006) failed to report the process of randomisation while the second study (Williams 1978) did not state the methods used to conceal allocation of treatment. The study by Lastória was open label and therefore at high risk of performance bias (Lastória 2006). Both study authors accounted for all missing data and reported data on all primary and secondary outcomes and therefore minimised the chances of attrition and performance bias. The two studies included in this review were based on relatively small sample sizes. The effect estimates from our results were imprecise and the confidence intervals were compatible with both benefit and harm.

Potential biases in the review process

None of the authors of this review were involved in any of the included or excluded studies. Furthermore, none have any commercial or other conflict of interest. The search was as comprehensive as possible, and all studies were independently assessed for inclusion by two review authors. We are confident that we have included all relevant studies and we have attempted to reduce bias in the review process. However, the possibility remains that we may have missed studies which have not been published.

Agreements and disagreements with other studies or reviews

Many studies have measured the effectiveness of drug prophylaxis on the prevention of VTE after surgery. However, the majority of these have been conducted in patients undergoing hip or knee replacement. Other studies on more general types of surgery have been done but specific data for patients undergoing amputation is rarely presented. Research on mechanical forms of prophylaxis in patients with amputation is scarce. To date, no systematic review has attempted to assess the effectiveness of prophylaxis in the prevention of VTE specifically in patients undergoing amputation.

Authors' conclusions

Implications for practice

Patients undergoing major lower limb amputation are at high risk of VTE and because of this there is a strong case for using preventative measures. However, as only two studies were included in this review, each comparing different interventions, there is insufficient evidence to make any conclusions regarding the most effective thromboprophylaxis regimen in patients undergoing lower limb amputation whether that be one drug alone or a combination of drug and compression devices.

Implications for research

The lack of studies in this systematic review confirms the need for methodologically sound and large randomised controlled trials. Future research should test the available forms of prophylaxis to find the most effective strategy, whether that be pharmacological prophylaxis alone or in combination with mechanical devices. Moreover, the acceptability of such interventions needs to be measured. Thus, any future studies should also analyse the secondary effects of such interventions, including adverse side effects and quality of life.

Acknowledgements

Thanks to Karen Welch (TSC), Cochrane Peripheral Vascular Disease Group, for conducting the search for the studies and to all the other members of the group for their assistance in this review.

Data and analyses

Download statistical data

Comparison 1. Unfractionated heparin versus low molecular weight heparin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Deep vein thrombosis (DVT)1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 1.1.

Comparison 1 Unfractionated heparin versus low molecular weight heparin, Outcome 1 Deep vein thrombosis (DVT).

Comparison 2. Heparin versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Pulmonary embolism1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
1.1 Above knee amputation1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 Below knee amputation1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 2.1.

Comparison 2 Heparin versus placebo, Outcome 1 Pulmonary embolism.

Appendices

Appendix 1. CENTRAL search strategy

#1MeSH descriptor: [Thrombosis] this term only1176
#2MeSH descriptor: [Thromboembolism] this term only992
#3MeSH descriptor: [Venous Thromboembolism] this term only275
#4MeSH descriptor: [Venous Thrombosis] explode all trees2164
#5(thrombo* or thrombus* or embol*):ti,ab,kw20603
#6MeSH descriptor: [Pulmonary Embolism] explode all trees857
#7PE or DVT or VTE:ti,ab,kw2158
#8((vein* or ven*) near thromb*):ti,ab,kw4960
#9blood flow stasis or "vein stasis*" or "venous stasis" or "blood clot"461
#10#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #921993
#11MeSH descriptor: [Amputation] explode all trees308
#12MeSH descriptor: [Amputation, Traumatic] explode all trees16
#13MeSH descriptor: [Amputees] explode all trees60
#14leg near/3 amput*84
#15extrem* near/3 amput*115
#16limb near/3 amput*248
#17transfemoral or transtibial:ti,ab,kw (Word variations have been searched)146
#18knee near/3 amput*118
#19disarticulat*14
#20exarticulat*1
#21#11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20777
#22#10 and #21 in Trials51
#23MeSH descriptor: [Anticoagulants] explode all trees3457
#24anticoagul* or anti-coagu*6185
#25*warfarin or (vitamin near/3 antagonist*) or VKA or Nicoumalone or phenindione or acenocoumarol* or Sinthrome or dicoumarol* or nicoumalone or phenprocoumon or Marcoumar or Marcumar or Falithrom or AVK or bishydroxycoumarin* or couma* or phenprocoumon* or aldocumar or carfin or jantoven or kumatox or lawarin or marevan or prothromadin or sofarin or tedicumar or tintorane or waran or warfant or warfilone or warnerin2900
#26LMWH or UFH or heparin or nadroparin* or fraxiparin* or enoxaparin7977
#27Clexane or klexane or lovenox or dalteparin or Fragmin or ardeparin635
#28normiflo or tinzaparin or logiparin or Innohep or certoparin or sandoparin or reviparin or clivarin*376
#29danaproid or danaparoid or antixarin or ardeparin* or bemiparin*108
#30Zibor or cy 222 or embolex or monoembolex or parnaparin*98
#31rd 11885 or tedelparin or Kabi-2165 or Kabi 216568
#32emt-966 or emt-967 or "pk-10 169" or pk-10169 or pk10169 or cy-216 or cy21680
#33seleparin* or tedegliparin or seleparin* or tedegliparin*12
#34wy90493 or "wy 90493" or "kb 101" or kb10123
#35lomoparan or orgaran or parnaparin or fluxum or lohepa or lowhepa or "op 2123" or parvoparin or AVE502690
#36#23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #3512641
#37MeSH descriptor: [Bandages] explode all trees2017
#38stocking* or hosier* or tight* or sock* or bandag*4525
#39jobst or surepress or activa or kendall or elbeo or levante or lloveras or cette or sigvaris or solidea or medilast or VenoTrain* or Ulcertec or ComfortPro or Comfort-Pro or "Ulcer Kit"723
#40MeSH descriptor: [Intermittent Pneumatic Compression Devices] this term only79
#41compres* or ICD6162
#42foot near/3 impulse11
#43#37 or #38 or #39 or #40 or #41 or #4210506
#44MeSH descriptor: [Factor Xa] explode all trees and with qualifiers: [Antagonists & inhibitors - AI]182
#45Factor X* near/4 (antag* or inhib* or block*):ti,ab,kw (Word variations have been searched)18432
#46FX* near/4 (antag* or inhib* or block*):ti,ab,kw (Word variations have been searched)30
#4710* near/4 (antag* or inhib* or block*)2692
#48fondapar* or Arixtra:ti,ab,kw (Word variations have been searched)176
#49idraparinux or "SANORG 34006" or Sanorg-34006 or Sanorg34006 or SSR-126517 or SSR126517:ti,ab,kw (Word variations have been searched)24
#50Idrabiotaparinux or SSR-126517-E:ti,ab,kw (Word variations have been searched)9
#51*arinux:ti,ab,kw (Word variations have been searched)204
#52#44 or #45 or #46 or #47 or #48 or #49 or #50 or #5120868
#53rivaroxaban or Xarelto:ti,ab,kw (Word variations have been searched)108
#54Bay-597939 or Bay597939:ti,ab,kw (Word variations have been searched)0
#55betrixaban or PRT054021:ti,ab,kw (Word variations have been searched)5
#56apixaban:ti,ab,kw (Word variations have been searched)49
#57BMS-562247 or BMS-562247 or ELIQUIS:ti,ab,kw (Word variations have been searched)0
#58*aban:ti,ab,kw (Word variations have been searched)352
#59DU-176b or DU176b:ti,ab,kw (Word variations have been searched)8
#60PRT-054021 or PRT-054021:ti,ab,kw (Word variations have been searched)0
#61YM150 or YM-150 or LY517717 or LY-517717 or DU-176b or DU176*:ti,ab,kw (Word variations have been searched)22
#62GW813893 or "Tak 442" or TAK442 or PD0348292 or GSK-813893 or GSK813893:ti,ab,kw (Word variations have been searched)1
#63#53 or #54 or #55 or #56 or #57 or #58 or #59 or #60 or #61 or #62372
#64MeSH descriptor: [Antithrombins] explode all trees194
#65MeSH descriptor: [Hirudin Therapy] explode all trees79
#66thrombin near/3 inhib*:ti,ab,kw (Word variations have been searched)468
#67hirudin*:ti,ab,kw (Word variations have been searched)326
#68*hirudin*:ti,ab,kw (Word variations have been searched)328
#69desirudin or bivalirudin or Angiomax or Angiox or hirulog:ti,ab,kw (Word variations have been searched)189
#70dabigatran or Pradaxa or Rendix:ti,ab,kw (Word variations have been searched)101
#71BIBR-953* or BIBR953* or BIBR-1048 or BIBR1048:ti,ab,kw (Word variations have been searched)3
#72ximelagatran or Exanta or Exarta or melagatran:ti,ab,kw (Word variations have been searched)155
#73ximelagatran or Exanta or Exarta or melagatran:ti,ab,kw (Word variations have been searched)155
#74argatroban or napsagatran or argatra or novastan:ti,ab,kw (Word variations have been searched)70
#75lepirudin or Refludan:ti,ab,kw (Word variations have been searched)18
#76MD805 or MD-805:ti,ab,kw (Word variations have been searched)7
#77*gatran:ti,ab,kw (Word variations have been searched)275
#78AZD0837 or AZD-0837:ti,ab,kw (Word variations have been searched)6
#79#64 or #65 or #66 or #67 or #68 or #69 or #70 or #71 or #72 or #73 or #74 or #75 or #76 or #77 or #78981
#80MeSH descriptor: [Platelet Aggregation Inhibitors] explode all trees2715
#81MeSH descriptor: [Phosphodiesterase Inhibitors] explode all trees882
#82phosphodiesterase near/3 inhibitor:ti,ab,kw (Word variations have been searched)1123
#83platelet near/3 inhibitor:ti,ab,kw (Word variations have been searched)2908
#84antiplatelet or anti-platelet or antiaggreg or anti-aggreg2015
#85MeSH descriptor: [Tetrazoles] explode all trees2277
#86cilosta*:ti,ab,kw (Word variations have been searched)264
#87pletal or pletaal:ti,ab,kw (Word variations have been searched)4
#8873963-72-12
#89OPC-13013 or OPC13013:ti,ab,kw (Word variations have been searched)5
#90((cyclooxygenase or ADP) near/3 inhib*)1837
#91aspirin8000
#92(acetyl near/3 salicylic) or ASA or acetylsalicyclic6885
#93clopidogrel* or Plavix1410
#94prasugrel or Effient or Efient or Prasita or Ticagrelor or Cangrelor or Portola or PRT060 or Brilinta170
#95ticlopidine or Ticlid or trapidil or thienopyridine1583
#96dipyridamo* or Persantin*1188
#97glycoprotein near/3 (antagonist or inhibitor)497
#98GR144053 or GR-144053 or abciximab or tirofiban or eftifibatid or eptifibatide930
#99ReoPro or Integrilin or Aggrastat173
#100terutroban15
#101picotamide62
#102satigrel15
#103#80 or #81 or #82 or #83 or #84 or #85 or #86 or #87 or #88 or #89 or #90 or #91 or #92 or #93 or #94 or #95 or #96 or #97 or #98 or #99 or #100 or #101 or #10222331
#104#22 and (#36 or #43 or #52 or #63 or #79 or #103) in Trials22
#105#21 and (#36 or #43 or #52 or #63 or #79 or #103) in Trials121
#106#104 or #105121

Contributions of authors

LR: drafted the protocol, selected studies for inclusion, assessed the quality of studies, performed data analysis and wrote the review.
AR: contributed to the protocol, selected studies for inclusion, assessed the quality of studies and contributed to the text of the review.

Declarations of interest

None known

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • National Institute for Health Research (NIHR), UK.

    The authors are supported by a programme grant from the NIHR.

  • Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.

    The PVD Group editorial base is supported by the Chief Scientist Office.

  • National Institute for Health Research (NIHR), UK.

    The PVD Group editorial base is supported by a programme grant from the NIHR.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Lastória 2006

Methods

Study design: Randomised open-label, clinical trial

Method of randomisation: Serial numbered envelopes

Exclusions post-randomisation: None

Lost to follow up: None

Participants

Country: Brazil

Setting: Hospital

Number: 75

Age: 18 - 86 years

Sex: 59 M, 16 F

Inclusion criteria: Patients over 18 years undergoing elective or emergency lower-limb amputation for critical limb ischaemia

Exclusion criteria: Previous venous thromboembolism, refusal to participate, contra-indication for anticoagulant prophylaxis

Interventions

Treatment: Enoxaparin 40 mg/day

Control: 5000 IU unfractionated heparin twice a day

Duration: Prophylaxis started 12 hours before surgery or, in emergency cases, on the first postoperative day and continued during period of hospitalisation

Outcomes

Primary: Deep vein thrombosis diagnosed by abnormal venous flow and evidence of intraluminal thrombi

Secondary: Bleeding complications

Diagnosis: Evaluation of DVT performed daily by clinical examination and by duplex scanning before and 5 to 8 days after surgery. DVT confirmed by compression ultrasonography

NotesMechanical prophylaxis was not used in this study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "Patients were randomized"

Comment: Method of randomisation not described. Insufficient information to permit judgement of 'low risk' or 'high risk'

Allocation concealment (selection bias)Low risk

Quote: "Serial numbered envelopes prepared by someone not involved in the study"

Comment: Low risk

Blinding of participants and personnel (performance bias)
All outcomes
High risk

Quote: "open label"

Comment: No blinding of study participants and personnel and therefore the study is at a high risk of performance bias

Blinding of outcome assessment (detection bias)
All outcomes
Low risk

Quote: "duplex scanning was performed by two vascular ultrasonographists blinded to the prophylactic treatment prescribed for the patients"

Comment: Blinding of outcome assessors was performed and therefore the study is at a low risk of detection bias

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll pre-specified study outcomes are reported
Other biasLow riskThe study appears to be free from other sources of bias

Williams 1978

Methods

Study design: Randomised, double-blind trial

Method of randomisation: Random number table

Exclusions post-randomisation: 71 excluded due to inadequate compliance with the protocol

Lost to follow up: None

Participants

Country: USA

Setting: Hospital

Number: 213 (94 above-knee and 40 below-knee amputations)

Age: Mean age 64.5 years (range 23 - 87 years)

Sex: 182 M, 30 F

Inclusion criteria: Patients requiring hip surgery because of hip fracture, total hip replacement for joint disease, or major lower extremity amputation for the complications of ischaemic vascular disease

Exclusion criteria: No exclusion criteria reported

Interventions

Treatment: 10,000 USP units/ml beef lung sodium heparin

Control: Saline

Duration: 0.5 ml coded solution subcutaneously administered as soon as possible after admission of patients with hip fracture and about two hours before operations in patients requiring amputation or elective total hip replacement, continued every 12 hours for 2 weeks or until discharge

Outcomes

Primary: Acute pulmonary embolism, defined as an intraluminal defect or abrupt vessel cut-off (a new lobar, segmental or subsegmental perfusion defect not attributable to an infiltrate, pleural effusion, vascular congestion, or atelectasis on the chest roentgenogram)

Secondary: Death, postoperative bleeding

Diagnosis: Lung perfusion scan performed before operation and then at weekly intervals for duration of treatment. Pulmonary arteriography performed in patients who developed a new pulmonary perfusion defect identified on serial lung scans. Additional selective angiograms were performed in doubtful cases. Plain chest roentgenograms were used for assistance in interpretation of arteriograms and perfusion lung scans. Autopsy to examine pulmonary arterial vessels for thrombi to the third division

Notes

Seven participants studied during two separate hospitalisations (administered same treatment, it is unclear whether these participants have been double counted)

Mechanical prophylaxis was not used in this study

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "patients were assigned using a random number table"

Comment: Randomisation was performed

Allocation concealment (selection bias)Unclear riskComment: Method of allocation concealment not stated. Insufficient information to permit judgement of 'low risk' or 'high risk'
Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Quote: "patients were assigned in a blind manner. After all patients were categorized for pulmonary embolism, the drug code was broken"

Comment: Blinding of participants and study personnel ensured and blinding was not broken until after treatment and outcomes measured

Blinding of outcome assessment (detection bias)
All outcomes
Low risk

Quote: "At intervals of 6-12 weeks, JW and EE reviewed lung scans without knowledge of arteriographic results, patient symptomatology, or treatment received. All pulmonary arteriograms were reviewed by SG, JW and EE without knowledge of the treatment. At autopsy, the pulmonary arterial vessels were examined for thrombi by a pathologist who did not know what drug treatment had been given to the patient. After all patients were categorized for pulmonary embolism, the drug code was broken"

Comment: Blinding of outcome assessment ensured and blinding was not broken until after patients had outcomes measured

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll data are accounted for
Selective reporting (reporting bias)Low riskAll pre-specified study outcomes are reported
Other biasLow riskThe study appears to be free from other sources of bias

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Atkins 1978Authors do not report if there was a subgroup of patients who underwent amputation
Covey 1975Patients with amputations were excluded from this study
Di Serio 1985Study included patients with major thoracic, abdominal or pelvic surgery only
Haas 2005Study did not include patients with amputation, confirmed by personal communication with the author
Huttenen 1977Excluded as patients had major or medium sized abdominal, thoracic or urological procedures
Kakkar 1978No amputation
Kakkar 2005Study on patients with abdominal surgery only
Kill 1979No amputation
Mantz 2011Study did not include patients with amputation, confirmed by personal communication with the author
Nicolaides 1972No amputation
Pachter 1977Authors do not state what the control treatment was. Furthermore, the methods used to confirm diagnosis of DVT and PE are not reported
Strand 1975Selection based on the same criteria as study by Kakkar 2005 which included only patients with abdominal surgery

Ancillary