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

Abstract

Background

People 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 (e.g. heparin, factor Xa inhibitors, vitamin K antagonists, direct thrombin inhibitors, antiplatelets) is effective in preventing deep vein thrombosis (DVT), but is associated with an increased risk of bleeding. Mechanical prophylaxis (e.g. antiembolism stockings, intermittent pneumatic compression and foot impulse devices), on the other hand, is non‐invasive and has minimal side effects. However, mechanical prophylaxis is not always appropriate for people with contraindications such as peripheral arterial disease (PAD), arteriosclerosis or bilateral lower limb amputations. It is important to determine the most effective thromboprophylaxis for people undergoing major amputation and whether this is one treatment alone or in combination with another. This is an update of the review first published in 2013.

Objectives

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

Search methods

The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase and Cumulative Index to Nursing and Allied Health Literature databases, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 5 November 2019. We planned to undertake reference checking of identified trials to identify additional studies. We did not apply any language restrictions.

Selection criteria

We included randomised controlled trials and quasi‐randomised controlled trials which allocated people undergoing a major unilateral or bilateral amputation (e.g. hip disarticulation, transfemoral, knee disarticulation and transtibial) of the lower extremity to different types or regimens of thromboprophylaxis (including pharmacological or mechanical prophylaxis) or placebo.

Data collection and analysis

Two review authors independently selected studies, extracted data and assessed risk of bias. We resolved any disagreements by discussion. Outcomes of interest were VTE (DVT and pulmonary embolism (PE)), mortality, adverse events and bleeding. We used GRADE criteria to assess the certainty of the evidence. The two included studies compared different treatments, so we could not pool the data in a meta‐analysis.

Main results

We did not identify any eligible new studies for this update. Two studies with a combined total of 288 participants met the inclusion criteria for this review.

Unfractionated heparin compared to low molecular weight heparin

One study compared unfractionated heparin with low molecular weight heparin and found no evidence of a difference between the treatments in the prevention of DVT (odds ratio (OR) 1.23, 95% confidence interval (CI) 0.28 to 5.35; 75 participants; very low‐certainty evidence). No bleeding events occurred in either group. Deaths and adverse events were not reported. This study was open‐label and therefore at a high risk of performance bias. Additionally, the study did not report the method of randomisation, so the risk of selection bias was unclear.

Heparin compared to placebo

In the second study, there was no evidence of a benefit from heparin use in preventing PE when compared to placebo (OR 0.84, 95% CI 0.35 to 2.01; 134 participants; low‐certainty evidence). Similarly, no evidence of improvement was detected when the level of amputation was considered, with a similar incidence of PE between the two treatment groups: above knee amputation (OR 0.79, 95% CI 0.31 to 1.97; 94 participants; low‐certainty evidence); and below knee amputation (OR 1.53, 95% CI 0.09 to 26.43; 40 participants; low‐certainty evidence). Ten participants died during the study; five underwent a post‐mortem and three were found to have had a recent PE, all of whom had been on placebo (low‐certainty evidence). Bleeding events were reported in less than 10% of participants in both treatment groups, but the study did not present specific data (low‐certainty evidence). There were no reports of other adverse events. This study did not report the methods used to conceal allocation of treatment, so it was unclear whether selection bias occurred. However, this study appeared to be free from all other sources of bias.

No study looked at mechanical prophylaxis.

Authors' conclusions

We did not identify any eligible new studies for this update. As we only included two studies in this review, each comparing different interventions, there is insufficient evidence to make any conclusions regarding the most effective thromboprophylaxis regimen in people undergoing lower limb amputation. Further large‐scale studies of good quality are required.

Plain language summary

Venous blood clot prevention in people undergoing lower limb amputation

Background

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 people 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 effective in preventing VTE, but also have 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, it is not clear which method is best for people having a lower limb amputation. This review aimed to establish the best method.

Study characteristics and main results

This review was first published in 2013, and we searched for any studies that have taken place since then (up to 5 November 2019). We did not find any eligible new studies for this update. The review includes the original two studies with a combined total of 288 participants.

One study compared two forms of the anticoagulant heparin. We found no evidence of a difference between unfractionated heparin and low molecular weight heparin in the prevention of DVT. None of the participants reported any 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 because the study did not adequately describe the process of randomly allocating treatment.

The second study found no evidence of a benefit for heparin compared with placebo in preventing a PE, 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 we could not analyse this. This study did not report the methods used to conceal how treatment was allocated, but we judged it 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.

Certainty of the evidence

The certainty of the evidence provided by these studies is very low for the comparison of unfractionated heparin against low molecular weight heparin, and low for the comparison of heparin against placebo. We downgraded the certainty of evidence due to the small size and low number of studies, and concerns over the methods used (risk of bias). Further larger studies are required to determine optimal venous thromboembolism prophylaxis in people undergoing major lower extremity amputation.

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 and 75 to 78% in Germany (NASDAB 2009; Spoden 2019). 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 2011), coupled with the 50% increase in the incidence of diabetes since 1997 (Kanavos 2012), means that the prevalence of PVD is likely to rise. Despite this, the prevalence of major lower limb amputation in England fell by 17% over the 10 year period from 2003 to 2013 (Ahmad 2016).

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 people having surgery (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 people after surgery (Keieme 2011). 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.

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, so 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). National Institute for Health and Care Excellence (NICE) guidelines recommend LMWH as first‐line pharmacological VTE prophylaxis unless contraindicated (NICE 2018). Heparin can be used as a prophylactic measure or to treat VTE. Heparin can cause serious side effects, including HIT, defined as a decrease in platelet count during or following exposure to heparin (Warkentin 2004). Evidence has shown that approximately 0.1% to 5% of people on heparin will develop HIT (Baglin 1997; Kelton 2002; Salter 2016). HIT is a serious and potentially life‐threatening condition (Franchini 2005).

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. Other factor Xa inhibitors, rivaroxaban and apixaban, are recommended as options for the prevention of VTE in people undergoing elective total hip or knee replacement (NICE 2018). A recent systematic review and network meta‐analysis showed that rivaroxaban and apixaban were the top two most effective strategies, respectively, for preventing DVT in people undergoing elective total knee replacement. (Lewis 2019). NICE published guidelines based on a review of evidence from four randomised controlled trials, that involved 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. This was supported by a recent meta‐analysis, where rivaroxaban had the second highest odds ratio for major bleeding, after fondaparinux (Lewis 2019).

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 receive heparin, which provides immediate anticoagulation (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).

Direct thrombin inhibitors

Direct thrombin inhibitors (DTIs) act as anticoagulants by directly inhibiting the enzyme thrombin and thus delaying blood clotting. The DTI dabigatran is recommended as an option for the prevention of VTE in people undergoing elective total hip or knee replacement (NICE 2018). 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.

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). Two recent meta‐analyses have shown that aspirin has similar efficacy and safety outcomes in people undergoing total hip and total knee replacements (Haykal 2019; Matharu 2020). 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.

Antiembolism stockings

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.

Intermittent pneumatic compression devices

IPCDs comprise inflatable cuffs placed around the foot, calf or thigh. The cuffs 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).

Foot impulse devices

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 (SIGN) recommends 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. This is an update of the review first published in 2013 (Robertson 2013a).

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

We included randomised controlled trials (RCTs) 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

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

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:

• One pharmacological prophylaxis versus another (e.g. LMWH versus UFH)

• One mechanical prophylaxis versus another (e.g. AES versus FID)

• Pharmacological prophylaxis versus mechanical prophylaxis

• Pharmacological plus mechanical prophylaxis versus mechanical prophylaxis alone

• 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):

  • type 0 ‐ no bleeding;

  • type 1 ‐ no actionable bleeding;

  • type 2 ‐ overt bleeding requiring either non‐surgical intervention or hospitalisation, or prompting evaluation;

  • 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);

  • type 5 ‐ fatal bleeding.

Search methods for identification of studies

Electronic searches

For this update, the Cochrane Vascular Information Specialist conducted systematic searches of the following databases for RCTs and controlled clinical trials without language, publication year or publication status restrictions:

• the Cochrane Vascular Specialised Register via the Cochrane Register of Studies (CRS‐Web searched 5 November 2019);

• the Cochrane Central Register of Controlled Trials (CENTRAL) Cochrane Register of Studies Online (CRSO 2019, Issue 10);

• MEDLINE (Ovid MEDLINE® Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE® Daily and Ovid MEDLINE®) (1 January 2017 to 5 November 2019);

• Embase Ovid (1 January 2017 to 5 November 2019);

• CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1 January 2017 to 5 November 2019);

• AMED Ovid (Allied and Complementary Medicine; 1 January 2017 to 5 November 2019).

The Information Specialist modelled search strategies for other databases on the search strategy designed for CENTRAL. Where appropriate, they were combined with adaptations of the highly sensitive search strategy designed by Cochrane for identifying RCTs and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Chapter 6, Lefebvre 2011). Search strategies for major databases are provided in Appendix 1.

The Information Specialist searched the following trials registries on 5 November 2019:

• the World Health Organization International Clinical Trials Registry Platform (who.int/trialsearch);

• ClinicalTrials.gov (clinicaltrials.gov).

Searching other resources

We translated non‐English language trials where required, and searched reference lists of identified studies.

Data collection and analysis

Selection of studies

Two review authors (DH, MT) screened the results of the 2019 search. These authors also independently assessed full‐text articles of potentially relevant studies. They resolved any disagreements by discussion or referred them to a third author for decision making (VP). For the previous version, one review author (LR) used the selection criteria to identify trials for inclusion and the second review author (AR) independently confirmed this selection (Robertson 2013a). We excluded studies which did not meet the inclusion criteria, and noted the reasons.

Data extraction and management

We did not identify any new eligible studies for this update. For the previous version of the review, two review authors (LR, AR) independently extracted the data. They recorded information about the trial design, type of amputation, baseline characteristics of participants and type of prophylaxis. They recorded non‐fatal and fatal VTE data as the primary outcome measures, and collected information on bleeding and deaths in accordance with the secondary outcome measures. They contacted the authors of included studies if they required further information or clarification. They resolved any disagreements about data extraction and management by discussion.

Assessment of risk of bias in included studies

We did not include any new studies in this update. For the previous version of the review, two review authors (LR, AR) independently used the Cochrane 'Risk of bias' tool to assess 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. They resolved any disagreements by discussion.

Measures of treatment effect

The analysis used intention‐to‐treat data from the individual clinical trials. As the primary and secondary outcomes were all binary measures, the effect measures were odds ratios (ORs) with 95% confidence intervals (CI).

Unit of analysis issues

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

Dealing with missing data

The authors of the previous version of this review sought information about dropouts, withdrawals and other missing data and, if not reported, contacted study authors 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, we only included two studies in this review. The studies tested different drugs and it was not possible to pool the data. Therefore, we could not assess heterogeneity between studies.

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 to aid the interpretation of the results (Sterne 2011). However, as we only included two studies in the review, it was not possible to test for funnel plot asymmetry.

Data synthesis

We did not identify any new eligible studies for this update. One of the previous review authors (LR) inputted the data into Review Manager (Review Manager 2014), and the second review author (AR) cross‐checked the data entry. They resolved any discrepancies by consulting the source publication. The previous authors planned to use a random‐effects model 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 we intended to investigate if data were available included:

• DVT or PE;

• indication for amputation;

• level of amputation (transfemoral, transtibial, exarticulation knee);

• history of VTE;

• diabetes;

• PVD (arterial, venous and lymphatic disease);

• smoking;

• body mass index (BMI);

• 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 we only included two studies in the review, it was not feasible to perform a sensitivity analysis.

Summary of findings and assessment of the certainty of the evidence

We prepared a 'Summary of findings' table to present the findings from our review for each comparison: 'Unfractionated heparin compared to low molecular weight heparin for venous thromboembolism prophylaxis in people undergoing major amputation of the lower extremity' (Table 1), and 'Heparin compared to placebo for venous thromboembolism prophylaxis in people undergoing major amputation of the lower extremity' (Table 2). We included the outcomes total VTE, DVT and PE, all cause mortality, adverse events and bleeding.

Summary of findings 1. Unfractionated heparin compared to low molecular weight heparin for venous thromboembolism prophylaxis in people undergoing major amputation of the lower extremity.

UFH compared to LMWH for VTE prophylaxis in people undergoing major amputation of the lower extremity
Patient or population: people undergoing major amputation of the lower extremity Setting: hospital Intervention: UFH Comparison: LMWH
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with LMWH	Risk with UFH
Total VTE (fatal and non‐fatal)	—	—	—	—	—	Only DVT reported
DVT (symptomatic, asymptomatic, non‐fatal) (5 to 8 days after surgery)	Study population		OR 1.23 (0.28 to 5.35)	75 (1 RCT)	⊕⊝⊝⊝ VERY LOW a	—
	98 per 1000	117 per 1000 (29 to 366)
PE (symptomatic, asymptomatic, non‐fatal)	—	—	—	—	—	Not reported
All cause mortality	—	—	—	—	—	Not reported
Adverse events	—	—	—	—	—	Not reported
Bleeding (timing not specified)	—	—	—	—	—	No events occurred in either treatment group
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; DVT: deep vein thrombosis; LMWH: low molecular weight heparin; PE: pulmonary embolism; OR: odds ratio; UFH: unfractionated heparin; VTE: venous thromboembolism
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

^aWe downgraded by three steps due to serious concerns in risk of bias (performance bias related to open‐label design), imprecision (due to small sample and event sizes) and confidence intervals that included both benefit and harm.

Summary of findings 2. Heparin compared to placebo for venous thromboembolism prophylaxis in people undergoing major amputation of the lower extremity.

Heparin compared to placebo for VTE prophylaxis in people undergoing major amputation of the lower extremity
Patient or population: people undergoing major amputation of the lower extremity Setting: hospital Intervention: heparin Comparison: placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with heparin
Total VTE (fatal and non‐fatal)	—	—	—	—	—	Only PE reported
DVT (symptomatic, asymptomatic, non‐fatal)	—	—	—	—	—	Not reported
PE (symptomatic, asymptomatic, non‐fatal) (timing not specified)	Study population		OR 0.84 (0.35 to 2.01)	134 (1 RCT)	⊕⊕⊝⊝ LOWa	—
	200 per 1000	174 per 1000 (80 to 334)
	Above knee amputation		OR 0.79 (0.31 to 1.97)	94 (1 RCT)	⊕⊕⊝⊝ LOWa	—
	293 per 1000	246 per 1000 (114 to 449)
	Below knee amputation		OR 1.53 (0.09 to 26.43)	40 (1 RCT)	⊕⊕⊝⊝ LOWa	—
	42 per 1000	62 per 1000 (4 to 535)
All cause mortality (timing not specified)	10 participants died during the study. Of these, 3/5 were reported to have had a recent PE following postmortem, all in the placebo group		—	40 (1 RCT)	⊕⊕⊝⊝ LOWb	—
Adverse events (timing not specified)	—	—	—	—	—	No adverse events reported apart from above PE
Bleeding (timing not specified)	The incidence of postoperative bleeding was less than 10% in both treatment groups (exact figures were not reported)		—	40 (1 RCT)	⊕⊕⊝⊝ LOWb	—
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; DVT: deep vein thrombosis; PE: pulmonary embolism; OR: odds ratio; VTE: venous thromboembolism
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

^aWe downgraded by two steps due to serious imprecision (due to small sample and event sizes) and confidence intervals that included both benefit and harm.

^bWe downgraded by two steps due to serious imprecision (due to small sample and event sizes) and study limitations (data not reported separately by treatment arm).

We used GRADEprofiler software to create the table (GRADEpro GDT). We used the GRADE criteria to rank the certainty of the evidence for each outcome based on risk of bias, inconsistency, indirectness, imprecision and publication bias (Guyatt 2008). We have provided a description for each step to downgrade the certainty of the evidence.

Results

Description of studies

Results of the search

Figure 1 shows the results of the search. For this update, we did not identify any new eligible studies and we excluded one new study (Casella 2015). We did not identify any ongoing studies or studies awaiting classification.

1.

Study flow diagram.

Included studies

We did not identify any new eligible studies for this update. The previous version included two studies (Lastória 2006; Williams 1978). The 'Characteristics of included studies' table describes the included studies.

One study was an open‐label RCT, which randomised 75 participants undergoing elective or emergency lower limb amputation for critical limb ischaemia (CLI) to receive subcutaneous UFH (5000 IU twice daily) or 40 mg enoxaparin daily (Lastória 2006). The study excluded people with a previous VTE or a contraindication to anticoagulant prophylaxis. Prophylaxis began 12 hours before elective surgery or, in emergency cases, on the first day postoperatively. The trialists assessed DVT by daily clinical examination and duplex ultrasound before surgery, and again between five and eight days after surgery. The study diagnosed DVT as an 'abnormal venous flow and evidence of intraluminal thrombi confirmed with compressive ultrasonography'. Of the 75 participants, 30 underwent an above‐knee amputation while the remaining 45 had a below‐knee amputation. The study randomised 34 participants to UFH and 41 to LMWH.

The second study was a randomised, double‐blind trial (Williams 1978). This randomised 134 participants undergoing lower extremity amputation for the complications of ischaemic vascular disease to receive low dose heparin or placebo. Sixty‐nine participants 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 participants (41 above knee and 24 below knee) received saline. Treatment started approximately two hours before surgery. Participants had lung perfusion scans before surgery and then at weekly intervals for the duration of treatment. Participants with a new pulmonary perfusion defect underwent pulmonary arteriography and, if that was unclear,
selective pulmonary angiography. PE was diagnosed if a new lobar, segmental or subsegmental perfusion defect appeared that was not attributable to an infiltrate, pleural effusion, vascular congestion or atelectasis appearing on the chest roentgenogram.

Excluded studies

Details of excluded studies are listed in the 'Characteristics of excluded studies' Table.

We identified one new excluded study (Casella 2015), bringing the total number of excluded studies to 13 (Atkins 1978; Casella 2015; Covey 1975; Di Serio 1985; Haas 2005; Huttenen 1977; Kakkar 1978; Kakkar 2005; Kill 1979; Mantz 2011; Nicolaides 1972; Pachter 1977; Strand 1975). We excluded 11 studies 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). We excluded one study as the authors did not state what the control treatment was, and did not report the methods of diagnosing DVT and PE (Pachter 1977). We excluded the new study by Casella 2015 as it randomised a heterogenous cohort of participants that included people undergoing amputations, but did not provide results specific to these participants. We contacted the authors to obtain participant level data, but did not receive any response.

Risk of bias in included studies

Figure 2 shows our judgements about each bias domain, presented as percentages across both of the included studies. Figure 3 depicts our assessments of each study's risk of bias in each domain.

2.

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

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, so we could not assess the risk of selection bias. The study by Williams 1978 used a random number table, so 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 and therefore at a high risk of performance bias (Lastória 2006). The remaining study blinded both study participants and personnel, so was at low risk of performance bias (Williams 1978). Both studies blinded outcome assessors to the treatment, and we deemed these to be at low risk of detection bias.

Incomplete outcome data

Both studies accounted for all incomplete outcome data, so we judged them to be at low risk of attrition bias.

Selective reporting

Both studies reported data on all prespecified primary and secondary outcomes. We therefore considered them to have a low risk of reporting bias.

Other potential sources of bias

The two studies appeared to be free from other sources of bias.

Effects of interventions

See: Table 1; Table 2

We included two studies in this review (Lastória 2006; Williams 1978). Lastória 2006 compared UFH against LMWH, and Williams 1978 compared UFH with a placebo. We did not include any studies on mechanical prophylaxis, such as compression devices.

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

The study by Lastória 2006 reported this comparison. Table 1 describes the outcomes.

Primary outcomes

Lastória 2006 did not report total VTE as an outcome.

Four of the 34 participants randomised to UFH had a DVT, compared to four of the 41 randomised to LMWH, showing no evidence of a difference between treatments (OR 1.23, 95% CI 0.28 to 5.35; 75 participants; very low‐certainty evidence; Analysis 1.1). The study authors reported the number of participants with above and below knee amputations, but did not present the results according to amputation type. We contacted the authors for this data, but they did not respond to our communication.

1.1. Analysis.

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

The study did not formally report PE events.

Secondary outcomes

No bleeding events occurred in either treatment group. The study did not formally report deaths or adverse events.

Heparin versus placebo

The study by Williams 1978 compared heparin with placebo. Table 2 describes the outcomes for this comparison.

Primary outcomes

Williams 1978 did not report total VTE or DVT as outcomes.

The incidence of PE was similar in the heparin (14/69) and placebo (13/65) groups showing no evidence of a difference between the groups (OR 0.84, 95% CI 0.35 to 2.01; 134 participants; low‐certainty evidence; Analysis 2.1). When analysed by type of amputation, heparin offered no improvement over placebo: above knee amputation OR of 0.79 (95% CI 0.31 to 1.97; 94 participants; low‐certainty evidence), below knee amputation OR of 1.53 (95% CI 0.09 to 26.43; 40 participants; low‐certainty evidence). No differences were detected between the subgroups (P = 0.66).

2.1. Analysis.

Comparison 2: Heparin versus placebo, Outcome 1: Pulmonary embolism

Secondary outcomes

Williams 1978 reported that 10 participants died during the study. Of those 10 people, five underwent a postmortem and three were found to have had a recent PE, all of whom were on placebo (low‐certainty evidence).

The incidence of postoperative bleeding was less than 10% in both treatment groups, although the paper did not report the exact figures and the study authors did not respond to requests for these data (low‐certainty evidence). The trialists removed one participant (randomised to placebo) prematurely from the study, due to excessive bleeding.

There were no reports of other adverse events.

Discussion

Summary of main results

We did not identify any eligible new studies for this update. Only two studies fulfilled the eligibility criteria for inclusion in this review. The study by Lastória 2006 compared the effectiveness of UFH with LMWH in the prevention of DVT up to eight days postamputation. There was no evidence of a difference between the two interventions in terms of DVT risk, and no bleeding occurred in the study population. The study by Williams 1978 was concerned with pulmonary embolism. There was no evidence of a benefit of heparin compared with placebo for this outcome, 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 people with lower limb amputation. The two studies tested different drugs and outcomes, so we could not pool their results 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, we did not include any study on mechanical prophylaxis in the review.

Quality of the evidence

The methodological quality of reporting in the studies was generally good. The risk of selection bias was unclear as one study failed to report the process of randomisation (Lastória 2006), while the second study did not state the methods used to conceal allocation of treatment (Williams 1978). The study by Lastória 2006 was open‐label, and therefore at high risk of performance bias. Both study authors accounted for all missing data and reported data on all their primary and secondary outcomes, so 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. Therefore, using the GRADE criteria, we downgraded the certainty of the evidence from high to very low for the comparison of UFH versus LWMH, and from high to low for the comparison of heparin versus placebo (see Table 1; Table 2).

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 two reviewers independently assessed all studies for inclusion. 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, including a recent Cochrane Review on prolonged LMWH VTE prophylaxis after abdomino‐pelvic surgery (Felder 2019). A significant portion of studies have been conducted in people undergoing hip or knee replacement, including a Cochrane Review which found that extended‐duration direct oral anticoagulants showed reduced symptomatic VTE and DVT (Forster 2016). A recent network meta‐analysis showed that rivaroxaban was the most effective strategy in preventing DVT in the total knee replacement population (Lewis 2019). Despite this evidence, specific data for people undergoing amputation are rarely presented. Research on mechanical forms of prophylaxis in people with amputation is scarce. To date, no other systematic review has attempted to assess the effectiveness of prophylaxis in the prevention of VTE specifically in people undergoing amputation. This is an update of the review first published in 2013.

Authors' conclusions

Implications for practice.

People undergoing major lower limb amputation are at high risk of venous thromboembolism, so there is a strong case for using preventative measures. However, as we only included two studies in this review and each compared different interventions, there is insufficient evidence to make any conclusions regarding the most effective thromboprophylaxis regimen in people 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 large and methodologically sound 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.

What's new

Date	Event	Description
22 May 2020	New search has been performed	New search run. No new studies included. One new study excluded.
22 May 2020	New citation required but conclusions have not changed	New search run. No new studies included. One new study excluded. New author team has taken over to update this review. Text revised to meet current Cochrane standards, including addition of 'Summary of findings' tables and GRADE assessment. No change to conclusions.

History

Protocol first published: Issue 5, 2013
Review first published: Issue 12, 2013

Appendices

Appendix 1. Database searches

Source	Search strategy	Hits retrieved
CENTRAL	#1 MESH DESCRIPTOR Thrombosis 1722 #2 MESH DESCRIPTOR Thromboembolism 1175 #3 MESH DESCRIPTOR Venous Thromboembolism 522 #4 MESH DESCRIPTOR Venous Thrombosis EXPLODE ALL TREES 2488 #5 (thrombo* or thrombus* or embol*):TI,AB,KY 53084 #6 MESH DESCRIPTOR Pulmonary Embolism EXPLODE ALL TREES 914 #7 (PE or DVT or VTE):TI,AB,KY 7457 #8 (((vein* or ven*) near thromb*)):TI,AB,KY 10534 #9 (blood flow stasis or "vein stasis*" or "venous stasis" or "blood clot"):TI,AB,KY 1967 #10 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 57740 #11 MESH DESCRIPTOR Amputation EXPLODE ALL TREES 393 #12 MESH DESCRIPTOR Amputation, Traumatic EXPLODE ALL TREES 49 #13 MESH DESCRIPTOR Amputees EXPLODE ALL TREES 106 #14 (leg near/3 amput*):TI,AB,KY 0 #15 (extrem* near/3 amput*):TI,AB,KY 0 #16 (limb near/3 amput*):TI,AB,KY 0 #17 (transfemoral or transtibial):TI,AB,KY 700 #18 (knee near/3 amput*):TI,AB,KY 0 #19 disarticulat*:TI,AB,KY 35 #20 exarticulat*:TI,AB,KY 0 #21 #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 1152 #22 MESH DESCRIPTOR Anticoagulants EXPLODE ALL TREES 10208 #23 (anticoagul* or anti‐coagu*):TI,AB,KY 12692 #24 (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 warnerin):TI,AB,KY 5663 #25 (LMWH or UFH or heparin or nadroparin* or fraxiparin* or enoxaparin):TI,AB,KY 12120 #26 (Clexane or klexane or lovenox or dalteparin or Fragmin or ardeparin):TI,AB,KY 947 #27 (normiflo or tinzaparin or logiparin or Innohep or certoparin or sandoparin or reviparin or clivarin*):TI,AB,KY 403 #28 (danaproid or danaparoid or antixarin or ardeparin* or bemiparin*):TI,AB,KY 137 #29 (Zibor or cy 222 or embolex or monoembolex or parnaparin*):TI,AB,KY 76 #30 (rd 11885 or tedelparin or Kabi‐2165 or Kabi 2165):TI,AB,KY 42 #31 (emt‐966 or emt‐967 or "pk‐10 169" or pk‐10169 or pk10169 or cy‐216 or cy216):TI,AB,KY 54 #32 (seleparin* or tedegliparin or seleparin* or tedegliparin*):TI,AB,KY 2 #33 (wy90493 or "wy 90493" or "kb 101" or kb101):TI,AB,KY 3 #34 (lomoparan or orgaran or parnaparin or fluxum or lohepa or lowhepa or "op 2123" or parvoparin or AVE5026):TI,AB,KY 90 #35 MESH DESCRIPTOR Bandages EXPLODE ALL TREES 2660 #36 (stocking* or hosier* or tight* or sock* or bandag*):TI,AB,KY 8394 #37 (jobst 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"):TI,AB,KY 480 #38 MESH DESCRIPTOR Intermittent Pneumatic Compression Devices EXPLODE ALL TREES 127 #39 (compres* or ICD):TI,AB,KY 13754 #40 (foot near/3 impulse):TI,AB,KY 0 #41 MESH DESCRIPTOR Factor Xa EXPLODE ALL TREES 125 #42 (Factor X* near4 (antag* or inhib* or block*)):TI,AB,KY 964 #43 (FX* near4 (antag* or inhib* or block*)):TI,AB,KY 85 #44 (10* near4 (antag* or inhib* or block*)):TI,AB,KY 1508 #45 (fondapar* or Arixtra):TI,AB,KY 402 #46 (idraparinux or "SANORG 34006" or Sanorg‐34006 or Sanorg34006 or SSR‐126517 or SSR126517):TI,AB,KY 43 #47 (Idrabiotaparinux or SSR‐126517‐E):TI,AB,KY 12 #48 *arinux:TI,AB,KY 1584886 #49 (rivaroxaban or Xarelto):TI,AB,KY 1413 #50 (Bay‐597939 or Bay597939):TI,AB,KY 0 #51 (betrixaban or PRT054021):TI,AB,KY 91 #52 apixaban:TI,AB,KY 811 #53 (BMS‐562247 or BMS‐562247 or ELIQUIS):TI,AB,KY 38 #54 *aban:TI,AB,KY 1584886 #55 (DU‐176b or DU176b):TI,AB,KY 49 #56 (PRT‐054021 or PRT‐054021):TI,AB,KY 0 #57 (YM150 or YM‐150 or LY517717 or LY‐517717 or DU‐176b or DU176*):TI,AB,KY 103 #58 (GW813893 or "Tak 442" or TAK442 or PD0348292 or GSK‐813893 or GSK813893):TI,AB,KY 7 #59 MESH DESCRIPTOR Antithrombins EXPLODE ALL TREES 1818 #60 MESH DESCRIPTOR Hirudin Therapy EXPLODE ALL TREES 75 #61 (thrombin near/3 inhib*):TI,AB,KY 0 #62 hirudin*:TI,AB,KY 455 #63 (desirudin or bivalirudin or Angiomax or Angiox or hirulog):TI,AB,KY 631 #64 (dabigatran or Pradaxa or Rendix):TI,AB,KY 991 #65 (BIBR‐953* or BIBR953* or BIBR‐1048 or BIBR1048):TI,AB,KY 48 #66 (ximelagatran or Exanta or Exarta or melagatran):TI,AB,KY 188 #67 (argatroban or napsagatran or argatra or novastan):TI,AB,KY 164 #68 (lepirudin or Refludan):TI,AB,KY 32 #69 (MD805 or MD‐805):TI,AB,KY 7 #70 *gatran:TI,AB,KY 1584886 #71 (AZD0837 or AZD‐0837):TI,AB,KY 23 #72 MESH DESCRIPTOR Platelet Aggregation Inhibitors EXPLODE ALL TREES 10377 #73 MESH DESCRIPTOR Phosphodiesterase Inhibitors EXPLODE ALL TREES 6770 #74 (phosphodiesterase near/3 inhibitor):TI,AB,KY 0 #75 (platelet near/3 inhibitor):TI,AB,KY 0 #76 (antiplatelet or anti‐platelet or antiaggreg or anti‐aggreg):TI,AB,KY 5590 #77 MESH DESCRIPTOR Tetrazoles EXPLODE ALL TREES 3345 #78 cilosta*:TI,AB,KY 774 #79 (pletal or pletaal):TI,AB,KY 33 #80 73963‐72‐1:TI,AB,KY 3 #81 (OPC‐13013 or OPC13013):TI,AB,KY 6 #82 (((cyclooxygenase or ADP) near3 inhib*)):TI,AB,KY 2378 #83 aspirin:TI,AB,KY 12692 #84 ((acetyl near3 salicylic) or ASA or acetylsalicyclic):TI,AB,KY 17671 #85 (clopidogrel* or Plavix):TI,AB,KY 5150 #86 (prasugrel or Effient or Efient or Prasita or Ticagrelor or Cangrelor or Portola or PRT060 or Brilinta):TI,AB,KY 2132 #87 (ticlopidine or Ticlid or trapidil or thienopyridine):TI,AB,KY 2622 #88 (dipyridamo* or Persantin*):TI,AB,KY 1363 #89 (glycoprotein near3 (antagonist or inhibitor)):TI,AB,KY 450 #90 (GR144053 or GR‐144053 or abciximab or tirofiban or eftifibatid or eptifibatide):TI,AB,KY 1644 #91 (ReoPro or Integrilin or Aggrastat):TI,AB,KY 236 #92 terutroban:TI,AB,KY 26 #93 picotamide:TI,AB,KY 46 #94 satigrel:TI,AB,KY 3 #95 #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52 OR #53 OR #54 OR #55 OR #56 OR #57 OR #58 OR #59 OR #60 OR #61 OR #62 OR #63 OR #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 #78 OR #79 OR #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 1584886 #96 #10 AND #21 AND #95 121 #97 #21 AND #95 1152 #98 #96 OR #97 1152 #99 01/11/2013 TO 05/11/2019:CD 877591 #100 #98 AND #99 734	5 November 2019: 734
Clinicaltrials.gov	Thrombosis OR Thromboembolism OR Venous Thromboembolism OR Venous Thrombosis OR Pulmonary Embolism | Amputation OR Amputation, Traumatic OR Amputees	5 November 2019: 1
ICTRP Search Portal	1 Thrombosis OR Thromboembolism OR Venous Thromboembolism OR Venous Thrombosis OR Pulmonary Embolism AND 2 Amputation OR Amputation, Traumatic OR Amputees	5 November 2019: 0
Medline (Ovid MEDLINE® Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE® Daily and Ovid MEDLINE®) 1946 to present 2017, 2018 and 2019 only)	1 Thrombosis/ 2 Thromboembolism/ 3 Venous Thromboembolism/ 4 Venous Thrombosis/ 5 (thrombo* or thrombus* or embol*).ti,ab. 6 exp Pulmonary Embolism/ 7 (DVT or VTE).ti,ab. 8 ((vein* or ven*) adj thromb*).ti,ab. 9 (blood flow stasis or "vein stasis*" or "venous stasis" or "blood clot").ti,ab. 10 or/1‐9 11 exp Amputation/ 12 exp Amputation, Traumatic/ 13 exp Amputees/ 14 (leg adj3 amput*).ti,ab. 15 (extrem* adj3 amput*).ti,ab. 16 (limb adj3 amput*).ti,ab. 17 (transfemoral or transtibial).ti,ab. 18 (knee* adj3 amput*).ti,ab. 19 disarticulat*.ti,ab. 20 exarticulat*.ti,ab. 21 or/11‐20 22 10 and 21 23 exp Anticoagulants/ 24 (anticoagul* or anti‐coagu*).ti,ab. 25 (warfarin or (vitamin adj3 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 warnerin).ti,ab. 26 (LMWH or UFH or heparin or nadroparin* or fraxiparin* or enoxaparin).ti,ab. 27 (Clexane or klexane or lovenox or dalteparin or Fragmin or ardeparin).ti,ab. 28 (normiflo or tinzaparin or logiparin or Innohep or certoparin or sandoparin or reviparin or clivarin*).ti,ab. 29 (danaproid or danaparoid or antixarin or ardeparin* or bemiparin*).ti,ab. 30 (Zibor or cy 222 or embolex or monoembolex or parnaparin*).ti,ab. 31 (rd 11885 or tedelparin or Kabi‐2165 or Kabi 2165).ti,ab. 32 (emt‐966 or emt‐967 or "pk‐10 169" or pk‐10169 or pk10169 or cy‐216 or cy216).ti,ab. 33 (seleparin* or tedegliparin or seleparin* or tedegliparin*).ti,ab. 34 (wy90493 or "wy 90493" or "kb 101" or kb101).ti,ab. 35 (lomoparan or orgaran or parnaparin or fluxum or lohepa or lowhepa or "op 2123" or parvoparin or AVE5026).ti,ab. 36 exp Bandages/ 37 (stocking* or hosier* or tight* or sock* or bandag*).ti,ab. 38 (jobst 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").ti,ab. 39 Intermittent Pneumatic Compression Devices/ 40 (compres* or ICD).ti,ab. 41 (foot adj3 impulse).ti,ab. 42 Factor Xa Inhibitors/ 43 (Factor X* adj4 (antag* or inhib* or block*)).ti,ab. 44 (FX* adj4 (antag* or inhib* or block*)).ti,ab. 45 (10* adj4 (antag* or inhib* or block*)).ti,ab. 46 (fondapar* or Arixtra).ti,ab. 47 (idraparinux or "SANORG 34006" or Sanorg‐34006 or Sanorg34006 or SSR‐126517 or SSR126517).ti,ab. 48 (Idrabiotaparinux or SSR‐126517‐E).ti,ab. 49 (rivaroxaban or Xarelto).ti,ab. 50 (Bay‐597939 or Bay597939).ti,ab. 51 (betrixaban or PRT054021).ti,ab. 52 apixaban.ti,ab. 53 (BMS‐562247 or BMS‐562247 or ELIQUIS).ti,ab. 54 (DU‐176b or DU176b).ti,ab. 55 (PRT‐054021 or PRT‐054021).ti,ab. 56 (YM150 or YM‐150 or LY517717 or LY‐517717 or DU‐176b or DU176*).ti,ab. 57 (GW813893 or "Tak 442" or TAK442 or PD0348292 or GSK‐813893 or GSK813893).ti,ab. 58 exp Antithrombins/ 59 exp Hirudin Therapy/ 60 (thrombin adj3 inhib*).ti,ab. 61 hirudin*.ti,ab. 62 (desirudin or bivalirudin or Angiomax or Angiox or hirulog).ti,ab. 63 (dabigatran or Pradaxa or Rendix).ti,ab. 64 (BIBR‐953* or BIBR953* or BIBR‐1048 or BIBR1048).ti,ab. 65 (ximelagatran or Exanta or Exarta or melagatran).ti,ab. 66 (argatroban or napsagatran or argatra or novastan).ti,ab. 67 (lepirudin or Refludan).ti,ab. 68 (MD805 or MD‐805).ti,ab. 69 (AZD0837 or AZD‐0837).ti,ab. 70 exp Platelet Aggregation Inhibitors/ 71 exp Phosphodiesterase Inhibitors/ 72 (phosphodiesterase adj3 inhibitor).ti,ab. 73 (platelet adj3 inhibitor).ti,ab. 74 (antiplatelet or anti‐platelet or antiaggreg or anti‐aggreg).ti,ab. 75 exp Tetrazoles/ 76 cilosta*.ti,ab. 77 (pletal or pletaal).ti,ab. 78 73963‐72‐1.ti,ab. 79 (OPC‐13013 or OPC13013).ti,ab. 80 ((cyclooxygenase or ADP) adj3 inhib*).ti,ab. 81 aspirin.ti,ab. 82 ((acetyl adj3 salicylic) or ASA or acetylsalicyclic).ti,ab. 83 (clopidogrel* or Plavix).ti,ab. 84 (prasugrel or Effient or Efient or Prasita or Ticagrelor or Cangrelor or Portola or PRT060 or Brilinta).ti,ab. 85 (ticlopidine or Ticlid or trapidil or thienopyridine).ti,ab. 86 (dipyridamo* or Persantin*).ti,ab. 87 (glycoprotein adj3 (antagonist or inhibitor)).ti,ab. 88 (GR144053 or GR‐144053 or abciximab or tirofiban or eftifibatid or eptifibatide).ti,ab. 89 (ReoPro or Integrilin or Aggrastat).ti,ab. 90 terutroban.ti,ab. 91 picotamide.ti,ab. 92 satigrel.ti,ab. 93 or/23‐92 94 22 and 93 95 randomized controlled trial.pt. 96 controlled clinical trial.pt. 97 randomized.ab. 98 placebo.ab. 99 drug therapy.fs. 100 randomly.ab. 101 trial.ab. 102 groups.ab. 103 or/95‐102 104 exp animals/ not humans.sh. 105 103 not 104 106 94 and 105 107 (2017* or 2018* or 2019*).ed. 108 106 and 107 109 21 and 93 110 105 and 107 and 109 111 108 or 110	5 November 2019: 155
Embase 1974 to present 2017, 2018 and 2019 only)	1 thrombosis/ 2 thromboembolism/ 3 venous thromboembolism/ 4 vein thrombosis/ 5 (thrombo* or thrombus* or embol*).ti,ab. 6 lung embolism/ 7 (DVT or VTE).ti,ab. 8 ((vein* or ven*) adj thromb*).ti,ab. 9 (blood flow stasis or "vein stasis*" or "venous stasis" or "blood clot").ti,ab. 10 or/1‐9 11 exp amputation/ 12 exp traumatic amputation/ 13 exp amputee/ 14 (leg adj3 amput*).ti,ab. 15 (extrem* adj3 amput*).ti,ab. 16 (limb adj3 amput*).ti,ab. 17 (transfemoral or transtibial).ti,ab. 18 (knee* adj3 amput*).ti,ab. 19 disarticulat*.ti,ab. 20 exarticulat*.ti,ab. 21 or/11‐20 22 10 and 21 23 exp anticoagulant agent/ 24 (anticoagul* or anti‐coagu*).ti,ab. 25 (warfarin or (vitamin adj3 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 warnerin).ti,ab. 26 (LMWH or UFH or heparin or nadroparin* or fraxiparin* or enoxaparin).ti,ab. 27 (Clexane or klexane or lovenox or dalteparin or Fragmin or ardeparin).ti,ab. 28 (normiflo or tinzaparin or logiparin or Innohep or certoparin or sandoparin or reviparin or clivarin*).ti,ab. 29 (danaproid or danaparoid or antixarin or ardeparin* or bemiparin*).ti,ab. 30 (Zibor or cy 222 or embolex or monoembolex or parnaparin*).ti,ab. 31 (rd 11885 or tedelparin or Kabi‐2165 or Kabi 2165).ti,ab. 32 (emt‐966 or emt‐967 or "pk‐10 169" or pk‐10169 or pk10169 or cy‐216 or cy216).ti,ab. 33 (seleparin* or tedegliparin or seleparin* or tedegliparin*).ti,ab. 34 (wy90493 or "wy 90493" or "kb 101" or kb101).ti,ab. 35 (lomoparan or orgaran or parnaparin or fluxum or lohepa or lowhepa or "op 2123" or parvoparin or AVE5026).ti,ab. 36 exp bandage/ 37 (stocking* or hosier* or tight* or sock* or bandag*).ti,ab. 38 (jobst 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").ti,ab. 39 intermittent pneumatic compression device/ 40 (compres* or ICD).ti,ab. 41 (foot adj3 impulse).ti,ab. 42 blood clotting factor 10a inhibitor/ 43 (Factor X* adj4 (antag* or inhib* or block*)).ti,ab. 44 (FX* adj4 (antag* or inhib* or block*)).ti,ab. 45 (10* adj4 (antag* or inhib* or block*)).ti,ab. 46 (fondapar* or Arixtra).ti,ab. 47 (idraparinux or "SANORG 34006" or Sanorg‐34006 or Sanorg34006 or SSR‐126517 or SSR126517).ti,ab. 48 (Idrabiotaparinux or SSR‐126517‐E).ti,ab. 49 (rivaroxaban or Xarelto).ti,ab. 50 (Bay‐597939 or Bay597939).ti,ab. 51 (betrixaban or PRT054021).ti,ab. 52 apixaban.ti,ab. 53 (BMS‐562247 or BMS‐562247 or ELIQUIS).ti,ab. 54 (DU‐176b or DU176b).ti,ab. 55 (PRT‐054021 or PRT‐054021).ti,ab. 56 (YM150 or YM‐150 or LY517717 or LY‐517717 or DU‐176b or DU176*:).ti,ab. 57 (GW813893 or "Tak 442" or TAK442 or PD0348292 or GSK‐813893 or GSK813893).ti,ab. 58 exp antithrombin/ 59 exp anticoagulant therapy/ 60 (thrombin adj3 inhib*).ti,ab. 61 hirudin*.ti,ab. 62 (desirudin or bivalirudin or Angiomax or Angiox or hirulog).ti,ab. 63 (dabigatran or Pradaxa or Rendix).ti,ab. 64 (BIBR‐953* or BIBR953* or BIBR‐1048 or BIBR1048).ti,ab. 65 (ximelagatran or Exanta or Exarta or melagatran).ti,ab. 66 (argatroban or napsagatran or argatra or novastan).ti,ab. 67 (lepirudin or Refludan).ti,ab. 68 (MD805 or MD‐805).ti,ab. 69 (AZD0837 or AZD‐0837).ti,ab. 70 exp antithrombocytic agent/ 71 exp phosphodiesterase inhibitor/ 72 (phosphodiesterase adj3 inhibitor).ti,ab. 73 (platelet adj3 inhibitor).ti,ab. 74 (antiplatelet or anti‐platelet or antiaggreg or anti‐aggreg).ti,ab. 75 exp tetrazole derivative/ 76 cilosta*.ti,ab. 77 (pletal or pletaal).ti,ab. 78 73963‐72‐1.ti,ab. 79 (OPC‐13013 or OPC13013).ti,ab. 80 ((cyclooxygenase or ADP) adj3 inhib*).ti,ab. 81 aspirin.ti,ab. 82 ((acetyl adj3 salicylic) or ASA or acetylsalicyclic).ti,ab. 83 (clopidogrel* or Plavix).ti,ab. 84 (prasugrel or Effient or Efient or Prasita or Ticagrelor or Cangrelor or Portola or PRT060 or Brilinta).ti,ab. 85 (ticlopidine or Ticlid or trapidil or thienopyridine).ti,ab. 86 (dipyridamo* or Persantin*).ti,ab. 87 (glycoprotein adj3 (antagonist or inhibitor)).ti,ab. 88 (GR144053 or GR‐144053 or abciximab or tirofiban or eftifibatid or eptifibatide).ti,ab. 89 (ReoPro or Integrilin or Aggrastat).ti,ab. 90 terutroban.ti,ab. 91 picotamide.ti,ab. 92 satigrel.ti,ab. 93 or/23‐92 94 22 and 93 95 randomized controlled trial/ 96 controlled clinical trial/ 97 random$.ti,ab. 98 randomization/ 99 intermethod comparison/ 100 placebo.ti,ab. 101 (compare or compared or comparison).ti. 102 ((evaluated or evaluate or evaluating or assessed or assess) and (compare or compared or comparing or comparison)).ab. 103 (open adj label).ti,ab. 104 ((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab. 105 double blind procedure/ 106 parallel group$1.ti,ab. 107 (crossover or cross over).ti,ab. 108 ((assign$ or match or matched or allocation) adj5 (alternate or group$1 or intervention$1 or patient$1 or subject$1 or participant$1)).ti,ab. 109 (assigned or allocated).ti,ab. 110 (controlled adj7 (study or design or trial)).ti,ab. 111 (volunteer or volunteers).ti,ab. 112 trial.ti. 113 or/95‐112 114 94 and 113 115 21 and 93 and 113 116 114 or 115	5 November 2019: 476
CINAHL 2017, 2018 and 2019 only)	S111 S109 AND S110 S110 EM 2017 OR EM 2018 OR EM 2019 S109 S93 AND S108 S108 S94 OR S95 OR S96 OR S97 OR S98 OR S99 OR S100 OR S101 OR S102 OR S103 OR S104 OR S105 OR S106 OR S107 S107 MH "Random Assignment" S106 MH "Triple‐Blind Studies" S105 MH "Double‐Blind Studies" S104 MH "Single‐Blind Studies" S103 MH "Crossover Design" S102 MH "Factorial Design" S101 MH "Placebos" S100 MH "Clinical Trials" S99 TX "multi‐centre study" OR "multi‐center study" OR "multicentre study" OR "multicenter study" OR "multi‐site study" S98 TX crossover OR "cross‐over" S97 AB placebo* S96 TX random* S95 TX trial* S94 TX "latin square" S93 S91 OR S92 S92 S21 AND S90 S91 S22 AND S90 S90 S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33 OR S34 OR S35 OR S36 OR S37 OR S38 OR S39 OR S40 OR S41 OR S42 OR S43 OR S44 OR S45 OR S46 OR S47 OR S48 OR S49 OR S50 OR S51 OR S52 OR S53 OR S54 OR S55 OR S56 OR S57 OR S58 OR S59 OR S60 OR S61 OR S62 OR S63 OR S64 OR S65 OR S66 OR S67 OR S68 OR S69 OR S70 OR S71 OR S72 OR S73 OR S74 OR S75 OR S76 OR S77 OR S78 OR S79 OR S80 OR S81 OR S82 OR S83 OR S84 OR S85 OR S86 OR S87 OR S88 OR S89 S89 TX satigrel S88 TX picotamide S87 TX terutroban S86 TX ReoPro or Integrilin or Aggrastat S85 TX GR144053 or GR‐144053 or abciximab or tirofiban or eftifibatid or eptifibatide S84 TX glycoprotein N3 (antagonist or inhibitor) S83 TX dipyridamo* or Persantin* S82 TX ticlopidine or Ticlid or trapidil or thienopyridine S81 TX prasugrel or Effient or Efient or Prasita or Ticagrelor or Cangrelor or Portola or PRT060 or Brilinta S80 TX clopidogrel* or Plavix S79 TX (acetyl N3 salicylic) or ASA or acetylsalicyclic S78 TX aspirin S77 TX (cyclooxygenase or ADP) N3 inhib* S76 TX OPC‐13013 or OPC13013 S75 TX 73963‐72‐1 S74 TX pletal or pletaal S73 TX cilosta* S72 TX Tetrazoles S71 TX antiplatelet or anti‐platelet or antiaggreg or anti‐aggreg S70 TX platelet N3 inhibitor S69 TX phosphodiesterase N3 inhibitor S68 (MH "Phosphodiesterase Inhibitors+") S67 (MH "Platelet Aggregation Inhibitors+") S66 TX AZD0837 or AZD‐0837 S65 TX MD805 or MD‐805 S64 TX lepirudin or Refludan S63 TX argatroban or napsagatran or argatra or novastan S62 TX ximelagatran or Exanta or Exarta or melagatran S61 TX BIBR‐953* or BIBR953* or BIBR‐1048 or BIBR1048 S60 TX dabigatran or Pradaxa or Rendix S59 TX desirudin or bivalirudin or Angiomax or Angiox or hirulog S58 TX hirudin* S57 TX Antithrombins S56 TX thrombin N3 inhib* S55 TX GW813893 or "Tak 442" or TAK442 or PD0348292 or GSK‐813893 or GSK813893 S54 TX YM150 or YM‐150 or LY517717 or LY‐517717 or DU‐176b or DU176* S53 TX DU‐176b or DU176b S52 TX BMS‐562247 or BMS‐562247 or ELIQUIS S51 TX apixaban S50 TX betrixaban or PRT054021 S49 TX Bay‐597939 or Bay597939 S48 TX rivaroxaban or Xarelto S47 TX Idrabiotaparinux or SSR‐126517‐E S46 TX idraparinux or "SANORG 34006" or Sanorg‐34006 or Sanorg34006 or SSR‐126517 or SSR126517 S45 TX fondapar* or Arixtra S44 TX 10* N4 (antag* or inhib* or block*) S43 TX FX* N4 (antag* or inhib* or block*) S42 TX Factor X* N4 (antag* or inhib* or block*) S41 TX foot adj3 impulse S40 TX compres* or ICD S39 (MH "Compression Garments") S38 TX jobst 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" S37 TX stocking* or hosier* or tight* or sock* or bandag* S36 (MH "Bandages and Dressings+") S35 TX lomoparan or orgaran or parnaparin or fluxum or lohepa or lowhepa or "op 2123" or parvoparin or AVE5026 S34 TX wy90493 or "wy 90493" or "kb 101" or kb101 S33 TX seleparin* or tedegliparin or seleparin* or tedegliparin* S32 TX emt‐966 or emt‐967 or "pk‐10 169" or pk‐10169 or pk10169 or cy‐216 or cy216 S31 TX rd 11885 or tedelparin or Kabi‐2165 or Kabi 2165 S30 TX Zibor or cy 222 or embolex or monoembolex or parnaparin* S29 TX danaproid or danaparoid or antixarin or ardeparin* or bemiparin* S28 TX normiflo or tinzaparin or logiparin or Innohep or certoparin or sandoparin or reviparin or clivarin* S27 TX Clexane or klexane or lovenox or dalteparin or Fragmin or ardeparin S26 TX LMWH or UFH or heparin or nadroparin* or fraxiparin* or enoxaparin S25 TX warfarin or (vitamin N3 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 warnerin S24 TX anticoagul* or anti‐coagu* S23 (MH "Anticoagulants+") S22 S10 AND S21 S21 S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 S20 TX exarticulat* S19 TX disarticulat* S18 TX knee* N3 amput* S17 TX transfemoral or transtibial S16 TX limb N3 amput* S15 TX extrem* N3 amput* S14 TX leg N3 amput* S13 (MH "Amputees") S12 (MH "Amputation, Traumatic") S11 (MH "Amputation+") S10 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 S9 TX blood flow stasis or "vein stasis*" or "venous stasis" or "blood clot" S8 TX ((vein* or ven*) N thromb*) S7 TX DVT or VTE S6 (MH "Pulmonary Embolism") S5 TX thrombo* or thrombus* or embol* S4 (MH "Venous Thrombosis") S3 (MH "Venous Thromboembolism") S2 (MH "Thromboembolism") S1 (MH "Thrombosis")	5 November 2019: 62
AMED (Allied and Complementary Medicine) 1985 to July 2018 (2017 AND 2018 ONLY)	1 Thrombosis/ 2 Thromboembolism/ 3 (thrombo* or thrombus* or embol*).ti,ab. 4 exp Pulmonary Embolism/ 5 (DVT or VTE).ti,ab. 6 ((vein* or ven*) adj thromb*).ti,ab. 7 (blood flow stasis or "vein stasis*" or "venous stasis" or "blood clot").ti,ab. 8 exp Amputation/ 9 (leg adj3 amput*).ti,ab. 10 (extrem* adj3 amput*).ti,ab. 11 (limb adj3 amput*).ti,ab. 12 (transfemoral or transtibial).ti,ab. 13 (knee* adj3 amput*).ti,ab. 14 disarticulat*.ti,ab. 15 exarticulat*.ti,ab. 16 exp Anticoagulants/ 17 (anticoagul* or anti‐coagu*).ti,ab. 18 (warfarin or (vitamin adj3 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 warnerin).ti,ab. 19 (LMWH or UFH or heparin or nadroparin* or fraxiparin* or enoxaparin).ti,ab. 20 (Clexane or klexane or lovenox or dalteparin or Fragmin or ardeparin).ti,ab. 21 (normiflo or tinzaparin or logiparin or Innohep or certoparin or sandoparin or reviparin or clivarin*).ti,ab. 22 (danaproid or danaparoid or antixarin or ardeparin* or bemiparin*).ti,ab. 23 (Zibor or cy 222 or embolex or monoembolex or parnaparin*).ti,ab. 24 (rd 11885 or tedelparin or Kabi‐2165 or Kabi 2165).ti,ab. 25 (emt‐966 or emt‐967 or "pk‐10 169" or pk‐10169 or pk10169 or cy‐216 or cy216).ti,ab. 26 (seleparin* or tedegliparin or seleparin* or tedegliparin*).ti,ab. 27 (wy90493 or "wy 90493" or "kb 101" or kb101).ti,ab. 28 (lomoparan or orgaran or parnaparin or fluxum or lohepa or lowhepa or "op 2123" or parvoparin or AVE5026).ti,ab. 29 exp Bandages/ 30 (stocking* or hosier* or tight* or sock* or bandag*).ti,ab. 31 (jobst 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").ti,ab. 32 Intermittent Pneumatic Compression Devices/ 33 (compres* or ICD).ti,ab. 34 (foot adj3 impulse).ti,ab. 35 Factor Xa Inhibitors/ 36 (Factor X* adj4 (antag* or inhib* or block*)).ti,ab. 37 (FX* adj4 (antag* or inhib* or block*)).ti,ab. 38 (10* adj4 (antag* or inhib* or block*)).ti,ab. 39 (fondapar* or Arixtra).ti,ab. 40 (idraparinux or "SANORG 34006" or Sanorg‐34006 or Sanorg34006 or SSR‐126517 or SSR126517).ti,ab. 41 (Idrabiotaparinux or SSR‐126517‐E).ti,ab. 42 (rivaroxaban or Xarelto).ti,ab. 43 (Bay‐597939 or Bay597939).ti,ab. 44 (betrixaban or PRT054021).ti,ab. 45 apixaban.ti,ab. 46 (BMS‐562247 or BMS‐562247 or ELIQUIS).ti,ab. 47 (DU‐176b or DU176b).ti,ab. 48 (PRT‐054021 or PRT‐054021).ti,ab. 49 (YM150 or YM‐150 or LY517717 or LY‐517717 or DU‐176b or DU176*:).ti,ab. 50 (GW813893 or "Tak 442" or TAK442 or PD0348292 or GSK‐813893 or GSK813893).ti,ab. 51 (thrombin adj3 inhib*:).ti,ab. 52 hirudin*.ti,ab. 53 (desirudin or bivalirudin or Angiomax or Angiox or hirulog).ti,ab. 54 (dabigatran or Pradaxa or Rendix).ti,ab. 55 (BIBR‐953* or BIBR953* or BIBR‐1048 or BIBR1048).ti,ab. 56 (ximelagatran or Exanta or Exarta or melagatran).ti,ab. 57 (argatroban or napsagatran or argatra or novastan).ti,ab. 58 (lepirudin or Refludan).ti,ab. 59 (MD805 or MD‐805).ti,ab. 60 (AZD0837 or AZD‐0837).ti,ab. 61 exp Platelet Aggregation Inhibitors/ 62 exp Phosphodiesterase Inhibitors/ 63 (phosphodiesterase adj3 inhibitor).ti,ab. 64 (platelet adj3 inhibitor).ti,ab. 65 (antiplatelet or anti‐platelet or antiaggreg or anti‐aggreg).ti,ab. 66 cilosta*.ti,ab. 67 (pletal or pletaal).ti,ab. 68 73963‐72‐1.ti,ab. 69 (OPC‐13013 or OPC13013).ti,ab. 70 ((cyclooxygenase or ADP) adj3 inhib*).ti,ab. 71 aspirin.ti,ab. 72 ((acetyl adj3 salicylic) or ASA or acetylsalicyclic).ti,ab. 73 (clopidogrel* or Plavix).ti,ab. 74 (prasugrel or Effient or Efient or Prasita or Ticagrelor or Cangrelor or Portola or PRT060 or Brilinta).ti,ab. 75 (ticlopidine or Ticlid or trapidil or thienopyridine).ti,ab. 76 (dipyridamo* or Persantin*).ti,ab. 77 (glycoprotein adj3 (antagonist or inhibitor)).ti,ab. 78 (GR144053 or GR‐144053 or abciximab or tirofiban or eftifibatid or eptifibatide).ti,ab. 79 (ReoPro or Integrilin or Aggrastat).ti,ab. 80 terutroban.ti,ab. 81 picotamide.ti,ab. 82 satigrel.ti,ab. 83 or/1‐7 84 or/8‐15 85 or/16‐82 86 83 and 84 and 85 87 84 and 85 88 86 or 87 89 exp CLINICAL TRIALS/ 90 RANDOM ALLOCATION/ 91 DOUBLE BLIND METHOD/ 92 Clinical trial.pt. 93 (clinic* adj trial*).tw. 94 ((singl* or doubl* or trebl* or tripl*) adj (blind* or mask*)).tw. 95 PLACEBOS/ 96 placebo*.tw. 97 random*.tw. 98 PROSPECTIVE STUDIES/ 99 or/89‐98 100 88 and 99 101 ("2017" or "2018" or "2019").yr. 102 100 and 101	5 November 2019: 2

Data and analyses

Comparison 1. Unfractionated heparin versus low molecular weight heparin.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Deep vein thrombosis (DVT)	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 2. Heparin versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Pulmonary embolism	1	134	Odds Ratio (M‐H, Random, 95% CI)	0.84 [0.35, 2.01]
2.1.1 Above knee amputation	1	94	Odds Ratio (M‐H, Random, 95% CI)	0.79 [0.31, 1.97]
2.1.2 Below knee amputation	1	40	Odds Ratio (M‐H, Random, 95% CI)	1.53 [0.09, 26.43]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Lastória 2006.

Study characteristics
Methods	Study design: randomised open‐label, clinical trial Method of randomisation: serial numbered envelopes Exclusions postrandomisation: none Lost to follow‐up: none
Participants	Country: Brazil Setting: hospital Number: 75 Age: 18 ‐ 86 years Sex: 59 male, 16 female Inclusion criteria: people over 18 years undergoing elective or emergency lower‐limb amputation for critical limb ischaemia Exclusion criteria: previous VTE, refusal to participate, contra‐indication for anticoagulant prophylaxis
Interventions	Treatment: enoxaparin 40 mg/day Control: 5000 IU UFH 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: DVT 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
Funding source	Paulista State University
Declarations of interest	No conflicts
Notes	Mechanical prophylaxis was not used in this study
Risk of bias
Bias	Authors' judgement	Support 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,so the study is at a low risk of detection bias
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Low risk	All prespecified study outcomes are reported
Other bias	Low risk	The study appears to be free from other sources of bias

Williams 1978.

Study characteristics
Methods	Study design: randomised, double‐blind trial Method of randomisation: random number table Exclusions postrandomisation: 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 to 87 years) Sex: 182 male, 30 female Inclusion criteria: people 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 people with hip fracture and about two hours before operations in people requiring amputation or elective total hip replacement, continued every 12 hours for 2 weeks or until discharge.
Outcomes	Primary: acute PE, 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 people 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.
Funding source	National Institutes of Health and Medical Research Service of Veterans Administration
Declarations of interest	‐
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
Bias	Authors' judgement	Support 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 risk	Comment: 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 participants had outcomes measured.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data are accounted for.
Selective reporting (reporting bias)	Low risk	All prespecified study outcomes are reported.
Other bias	Low risk	The study appears to be free from other sources of bias.

DVT: deep vein thrombosis
PE: pulmonary embolism
UFH: unfractionated heparin
VTE: venous thromboembolism

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Atkins 1978	Study authors did not report if there was a subgroup of participants who underwent amputation.
Casella 2015	Study authors did not report results specific to participants undergoing amputations.
Covey 1975	People with amputations were excluded from this study.
Di Serio 1985	Study included people with major thoracic, abdominal or pelvic surgery only.
Haas 2005	Study did not include people with amputation, confirmed by personal communication with the author.
Huttenen 1977	Excluded as participants had major or medium sized abdominal, thoracic or urological procedures.
Kakkar 1978	No amputation.
Kakkar 2005	Study on people with abdominal surgery only.
Kill 1979	No amputation.
Mantz 2011	Study did not include people with amputation, confirmed by personal communication with the author.
Nicolaides 1972	No amputation.
Pachter 1977	Authors do not state what the control treatment was. Furthermore, the methods used to confirm diagnosis of DVT and PE are not reported.
Strand 1975	Selection based on the same criteria as study by Kakkar 2005, which included only participants with abdominal surgery.

DVT: deep vein thrombosis
PE: pulmonary embolism

Differences between protocol and review

2020: In keeping with current Cochrane recommendations we have created a 'Summary of findings' table for this update and used GRADE criteria to assess the certainty of the evidence for each outcome.

Contributions of authors

DH: selected studies for inclusion, contacted authors for further details, created 'Summary of findings' tables, assessed studies using GRADE criteria, and updated the review
MT: selected studies for inclusion, assessed quality of studies using GRADE criteria, and updated the review
QT: updated the review
VP: resolved disagreements for study inclusion

Sources of support

Internal sources

• No sources of support supplied

External sources

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

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

Declarations of interest

DH: none known 
MT: none known
QT: none known
VP: none known

New search for studies and content updated (no change to conclusions)