Combined intermittent pneumatic leg compression and pharmacological prophylaxis for prevention of venous thromboembolism

Stavros Kakkos; George Kirkilesis; Joseph A Caprini; George Geroulakos; Andrew Nicolaides; Gerard Stansby; Daniel J Reddy

doi:10.1002/14651858.CD005258.pub4

. 2022 Jan 28;2022(1):CD005258. doi: 10.1002/14651858.CD005258.pub4

Combined intermittent pneumatic leg compression and pharmacological prophylaxis for prevention of venous thromboembolism

Stavros Kakkos ^1,^✉, George Kirkilesis ¹, Joseph A Caprini ^2,³, George Geroulakos ^4,⁵, Andrew Nicolaides ⁶, Gerard Stansby ⁷, Daniel J Reddy ⁸

Editor: Cochrane Vascular Group

PMCID: PMC8796751 PMID: 35089599

Abstract

Background

It is generally assumed by practitioners and guideline authors that combined modalities (methods of treatment) are more effective than single modalities in preventing venous thromboembolism (VTE), defined as deep vein thrombosis (DVT) or pulmonary embolism (PE), or both. This is the second update of the review first published in 2008.

Objectives

The aim of this review was to assess the efficacy of combined intermittent pneumatic leg compression (IPC) and pharmacological prophylaxis compared to single modalities in preventing VTE.

Search methods

The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and AMED databases, and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 18 January 2021. We searched the reference lists of relevant articles for additional studies.

Selection criteria

We included randomised controlled trials (RCTs) or controlled clinical trials (CCTs) of combined IPC and pharmacological interventions used to prevent VTE compared to either intervention individually.

Data collection and analysis

We independently selected studies, applied Cochrane's risk of bias tool, and extracted data. We resolved disagreements by discussion. We performed fixed‐effect model meta‐analyses with odds ratios (ORs) and 95% confidence intervals (CIs). We used a random‐effects model when there was heterogeneity. We assessed the certainty of the evidence using GRADE. The outcomes of interest were PE, DVT, bleeding and major bleeding.

Main results

We included a total of 34 studies involving 14,931 participants, mainly undergoing surgery or admitted with trauma. Twenty‐five studies were RCTs (12,672 participants) and nine were CCTs (2259 participants). Overall, the risk of bias was mostly unclear or high. We used GRADE to assess the certainty of the evidence and this was downgraded due to the risk of bias, imprecision or indirectness.

The addition of pharmacological prophylaxis to IPC compared with IPC alone reduced the incidence of symptomatic PE from 1.34% (34/2530) in the IPC group to 0.65% (19/2932) in the combined group (OR 0.51, 95% CI 0.29 to 0.91; 19 studies, 5462 participants, low‐certainty evidence). The incidence of DVT was 3.81% in the IPC group and 2.03% in the combined group showing a reduced incidence of DVT in favour of the combined group (OR 0.51, 95% CI 0.36 to 0.72; 18 studies, 5394 participants, low‐certainty evidence). The addition of pharmacological prophylaxis to IPC, however, increased the risk of any bleeding compared to IPC alone: 0.95% (22/2304) in the IPC group and 5.88% (137/2330) in the combined group (OR 6.02, 95% CI 3.88 to 9.35; 13 studies, 4634 participants, very low‐certainty evidence). Major bleeding followed a similar pattern: 0.34% (7/2054) in the IPC group compared to 2.21% (46/2079) in the combined group (OR 5.77, 95% CI 2.81 to 11.83; 12 studies, 4133 participants, very low‐certainty evidence).

Tests for subgroup differences between orthopaedic and non‐orthopaedic surgery participants were not possible for PE incidence as no PE events were reported in the orthopaedic subgroup. No difference was detected between orthopaedic and non‐orthopaedic surgery participants for DVT incidence (test for subgroup difference P = 0.19).

The use of combined IPC and pharmacological prophylaxis modalities compared with pharmacological prophylaxis alone reduced the incidence of PE from 1.84% (61/3318) in the pharmacological prophylaxis group to 0.91% (31/3419) in the combined group (OR 0.46, 95% CI 0.30 to 0.71; 15 studies, 6737 participants, low‐certainty evidence). The incidence of DVT was 9.28% (288/3105) in the pharmacological prophylaxis group and 5.48% (167/3046) in the combined group (OR 0.38, 95% CI 0.21 to 0.70; 17 studies; 6151 participants, high‐certainty evidence). Increased bleeding side effects were not observed for IPC when it was added to anticoagulation (any bleeding: OR 0.87, 95% CI 0.56 to 1.35, 6 studies, 1314 participants, very low‐certainty evidence; major bleeding: OR 1.21, 95% CI 0.35 to 4.18, 5 studies, 908 participants, very low‐certainty evidence).

No difference was detected between the orthopaedic and non‐orthopaedic surgery participants for PE incidence (test for subgroup difference P = 0.82) or for DVT incidence (test for subgroup difference P = 0.69).

Authors' conclusions

Evidence suggests that combining IPC with pharmacological prophylaxis, compared to IPC alone reduces the incidence of both PE and DVT (low‐certainty evidence). Combining IPC with pharmacological prophylaxis, compared to pharmacological prophylaxis alone, reduces the incidence of both PE (low‐certainty evidence) and DVT (high‐certainty evidence). We downgraded due to risk of bias in study methodology and imprecision. Very low‐certainty evidence suggests that the addition of pharmacological prophylaxis to IPC increased the risk of bleeding compared to IPC alone, a side effect not observed when IPC is added to pharmacological prophylaxis (very low‐certainty evidence), as expected for a physical method of thromboprophylaxis. The certainty of the evidence for bleeding was downgraded to very low due to risk of bias in study methodology, imprecision and indirectness. The results of this update agree with current guideline recommendations, which support the use of combined modalities in hospitalised people (limited to those with trauma or undergoing surgery) at risk of developing VTE. More studies on the role of combined modalities in VTE prevention are needed to provide evidence for specific patient groups and to increase our certainty in the evidence.

Plain language summary

Are inflatable sleeves and medication effective to prevent deep vein thrombosis and pulmonary embolism after surgery?

Key message

• The use of inflatable sleeves worn on the legs (intermittent pneumatic leg compression) plus medication may reduce the rate of new cases of blood clots in the lungs and legs compared to inflatable sleeves alone.

• The use of inflatable sleeves plus medication compared to medication alone reduces the rate of new cases of blood clots in the legs and may reduce new blood clots in the lungs.

• The addition of a medication to inflatable sleeves, may increase the risk of bleeding compared to inflatable sleeves alone.

Why is this question important?

Deep vein thrombosis (DVT) and pulmonary embolism are collectively known as venous thromboembolism, and occur when a blood clot develops inside the leg veins and travels to the lungs. They are possible complications of staying in hospital after surgery, trauma or other risk factors. These complications extend hospital stay and are associated with long‐term disability and death. Patients undergoing total hip or knee replacement (orthopaedic) surgery or surgery for colorectal cancer are at high risk of venous thromboembolism. Sluggish blood flow, increased blood clotting and blood vessel wall injury are factors that make it more likely that people will experience a blood clot. Treating more than one of these factors may improve prevention. Mechanical intermittent pneumatic leg compression involves wrapping the legs with inflatable sleeves or using foot pumps. These put gentle pressure on the legs and its veins, reducing sluggish blood flow, while medications such as aspirin and anticoagulants reduce blood clotting. These medications are known as pharmacological prophylaxis (drugs used to prevent blood clots). However, these medications can also increase the risk of bleeding. We wanted to find out if combining compression and medication to stop blood clots was more effective than either compression or medication alone.

What did we find?

We searched for studies that compared combined compression and medication against either compression or medication alone. We found 34 studies with a total of 14,931 participants. The mean age of participants, where reported, was 62.7 years. Most participants had either a high‐risk procedure or condition (orthopaedic surgery in 14 studies and urology, cardiothoracic, neurosurgery, trauma, general surgery, gynaecology or other types of participants in the remaining studies).

Compared to compression alone, compression plus medication was better by reducing the rate of new cases of pulmonary embolism (19 studies, 5462 participants). DVT was also reduced for compression combined with medication when compared with compression alone (18 studies, 5394 participants). The addition of a medication to compression, however, increased the risk of any bleeding compared to IPC alone, from 1% to 5.9%. Major bleeding followed a similar pattern, with an increase from 0.3% to 2.2%. Further analysis looking at different types of participants (orthopaedic and non‐orthopaedic participants) showed a similar risk for DVT. It was not possible to assess differences between subgroups for pulmonary embolism.

Compared with medication alone, combined compression and medication was better by reducing pulmonary embolism (15 studies with 6737 participants). DVT was also reduced in the combined compression and medication group (17 studies with 6151 participants). No differences were observed in rates of bleeding (six studies with 1314 participants). Further analysis looking at different subgroups of participants did not show any overall difference in incidence of pulmonary embolism or DVT between orthopaedic and non‐orthopaedic participants.

How certain are we in the evidence?

We found our confidence in the evidence ranged from high to very low. We had concerns on how the studies were carried out, because there were small numbers of clots overall and different definitions used for bleeding between the studies.

How up to date is this evidence?

This review updates our previous evidence. The evidence is current to January 2021.

Summary of findings

Background

It has been proposed that combined modalities are more effective than single modalities in preventing venous thromboembolism (VTE), defined as deep vein thrombosis (DVT) or pulmonary embolism (PE), or both. This is the second update of the review first published in 2008.

Description of the condition

Deep vein thrombosis (DVT), that is, the development of thrombi (blood clots) inside the deep veins of the legs (in most instances), is a potentially fatal disease as it can be complicated by pulmonary embolism (PE), resulting from the movement of thrombi from the leg veins to the pulmonary artery or its branches. The incidence of venous thromboembolism (VTE), DVT, PE or both, is still high despite the use of contemporary prophylactic measures. VTE risk is increased by the presence of certain risk factors, including, age, malignancy, immobilisation, and the type of surgery. High‐risk patients include those undergoing total hip or knee replacement, or surgery for colorectal cancer (McLeod 2001). Experts in the field have indicated that this and similar observations are the result of failed and also omitted prophylaxis (Goldhaber 2001; Piazza 2007). The most recent guidelines recommend combined pharmacological and mechanical prophylaxis in high‐risk groups, in an effort to maximise thromboprophylaxis (ASH 2019; Gould 2012; Nicolaides 2013). It is likely that mechanical methods increase the efficacy of thromboprophylaxis and reduce death and morbidity rates without increasing bleeding risk.

Description of the intervention

Intermittent pneumatic leg compression (IPC) involves wrapping the legs with inflatable sleeves, using commercially available devices. As a result of sleeve inflation, external pressure is exerted on the legs and its veins, resulting in an increase in blood flow and this reduction of blood stasis decreases the incidence of VTE. Pharmacological prophylaxis on the other hand is achieved by mostly small doses of anticoagulants given orally or subcutaneously; these also significantly reduce the incidence of VTE. Combined IPC and pharmacological prophylaxis in the form of dual modalities concurrently used for prevention of VTE may improve the efficacy of each method used alone.

How the intervention might work

Mechanical methods reduce VTE mainly by reducing venous stasis, while anticoagulants inhibit elements of the thrombosis cascade. Because single prophylactic modalities reduce but do not completely eliminate VTE, combined modalities are expected to reduce further the frequency of VTE because of their different mechanisms of action.

Why it is important to do this review

This is the second update of a Cochrane Review first published in 2008 (Kakkos 2008). VTE is the single most common, preventable cause of postoperative death. Better use of preventive resources is expected to reduce VTE events and mortality. Use of combined modalities is suggested by current guidelines in high‐risk patients, however the evidence supporting these recommendations requires better attention (Gould 2012; Nicolaides 2013). We performed this update to assess the breadth and strength of the best available evidence by pooling data from multiple studies to overcome the limitations of small and underpowered studies.

Objectives

The aim of this review was to assess the efficacy of combined intermittent pneumatic leg compression (IPC) and pharmacological prophylaxis compared to single modalities in preventing VTE.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) and controlled clinical trials (CCTs). We excluded studies with non‐standard designs, such as cross‐over trials and cluster‐randomised trials because they were deemed inappropriate in this context.

Types of participants

We included any type of hospitalised patient requiring prevention of venous thromboembolism (VTE) or at risk of developing VTE. We included participants undergoing surgery and trauma and intensive care unit (ICU) patients.

Types of interventions

We included studies that assessed the combined use of IPC (including foot pumps and devices inflating calf sleeves) and pharmacological prophylaxis (including unfractionated heparin and low molecular weight heparin) compared with IPC or pharmacological prophylaxis alone. We excluded studies that used IPC for a short period of time (that is, intraoperatively).

Types of outcome measures

Primary outcomes

Incidence of PE, assessed by pulmonary angiography or scintigraphy, computed tomography (CT), angiography and autopsy for PE
Incidence of DVT (symptomatic or asymptomatic), assessed by ascending venography, I‐125 fibrinogen uptake test and ultrasound scanning

Secondary outcomes

Bleeding: considered as a safety outcome and including all types reported, that is, any type
Major bleeding (as defined by the study authors, but usually located at the surgical site or in a critical organ or site, requiring intervention or transfusion of at least two units of blood, or leading to death), and fatal bleeding reported separately
Fatal PE, assessed by autopsy
Symptomatic DVT, assessed by ascending venography, I‐125 fibrinogen uptake test and ultrasound scanning

Search methods for identification of studies

Electronic searches

The Cochrane Vascular Information Specialist conducted systematic searches of the following databases for RCTs and CCTs without language, publication year or publication status restrictions.

Cochrane Vascular Specialised Register via the Cochrane Register of Studies (CRS‐Web searched on 18 January 2021)
Cochrane Central Register of Controlled Trials (CENTRAL) Cochrane Register of Studies Online (CRSO 2020, Issue 12)
MEDLINE (Ovid MEDLINE Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE) (searched from 3 May 2016 to 13 January 2021)
Embase Ovid (searched from 3 May 2016 to 18 January 2021)
CINAHL Ebsco (searched from 3 May 2016 to 18 January 2021)
AMED Ovid (searched from 3 May 2016 to 18 January 2021)

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 CCTs (as described in the Cochrane Handbook for Systematic Reviews of Interventions chapter 4, Lefebvre 2021). Search strategies for major databases are provided in Appendix 1.

The Information Specialist searched these trials registries on 18 January 2021:

World Health Organization International Clinical Trials Registry Platform (who.int/trialsearch);
ClinicalTrials.gov (clinicaltrials.gov).

Searching other resources

The review authors searched the reference lists of relevant articles and also similar systematic reviews and meta‐analyses to identify additional studies. We also carried out clinical trial database searches up to 12 July 2021. See Appendix 2.

Data collection and analysis

Selection of studies

For this update, two review authors (SK and GK) independently selected studies for inclusion on the basis of the use of combined mechanical IPC and pharmacological modalities. We resolved any disagreements by discussion.

Data extraction and management

For this update, two review authors (SK and GK) independently extracted the data. We used a data extraction form to record the type of patient or surgical procedure, total number of participants in the study (including those randomised, excluded and also withdrawn), the interventions used, the number of participants who reached an endpoint (DVT or PE) and the methodology used to establish this. A third review author (JC) arbitrated any disagreements.

Assessment of risk of bias in included studies

For this update, we assessed the methodological quality of included studies using Cochrane's risk of bias tool (RoB 1). SK and GK independently performed the assessment according to Higgins 2011. We assessed the following domains: selection bias (random sequence generation, allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessment), attrition bias (incomplete outcome data), reporting bias (selective reporting) and other bias. We classified the domains as low risk, high risk, or unclear risk according to Higgins 2011. We resolved any disagreements after discussion.

Measures of treatment effect

We performed separate analyses for the interventions of IPC versus combined modalities, and pharmacological prophylaxis versus combined modalities for the outcomes of PE and DVT. We used odds ratios (ORs) with 95% confidence intervals (CIs) for the assessment of dichotomous outcomes. None of our outcomes of interest were reported as continuous data.

Unit of analysis issues

We excluded studies with non‐standard designs, such as cross‐over trials and cluster‐randomised trials. The individual participant was the unit of analysis.

Dealing with missing data

In case of missing participants due to dropout, we used intention‐to‐treat analysis. Where necessary, we contacted study authors to request that they provided any missing information.

Assessment of heterogeneity

We assessed statistical heterogeneity with the I² test (Higgins 2003). We considered I² test levels exceeding 50% as substantial heterogeneity to justify the use of random‐effects model analysis (Deeks 2021). We also considered the magnitude and direction of effects and the strength of evidence for heterogeneity (e.g. P value from the Chi² test, or a CI for I² test).

Assessment of reporting biases

We assessed publication bias with funnel plots when 10 or more studies were included in a comparison and contributed to the effect estimate; as described in the Cochrane Handbook for Systematic Reviews of Interventions (Page 2021). Where the number of studies in each comparison was not greater than 10 the plots lack the power to distinguish chance from real asymmetry (Egger 1997).

Data synthesis

We used fixed‐effect models for each meta‐analysis to pool data, unless there was evidence of heterogeneity, in which case we used a random‐effects model to calculate the ORs and 95% CIs (see Assessment of heterogeneity). We only undertook meta‐analyses when it was meaningful to do so. That is, if the treatments, participants, and the underlying clinical question were similar enough for pooling to make sense. If meta‐analysis was not possible, we planned to report the results using a narrative synthesis.

Subgroup analysis and investigation of heterogeneity

To investigate heterogeneity, we performed subgroup analysis of the primary outcomes by:

surgery type (orthopaedic surgery compared to non‐orthopaedic surgery or other conditions);
type of IPC (foot IPC and other than foot IPC).

Sensitivity analysis

We planned to perform sensitivity analysis of the primary outcomes by excluding studies with a high risk for bias in any one or more domains, based on the RoB 1, and by excluding CCTs, in order to test the robustness of the evidence. We also planned to perform sensitivity analysis of the primary outcomes by excluding studies with medical patients.

Summary of findings and assessment of the certainty of the evidence

We created summary of findings tables for the comparisons of 'IPC plus pharmacological prophylaxis versus IPC alone' (Table 1) and 'IPC plus pharmacological prophylaxis versus pharmacological prophylaxis alone' (Table 2). We used GRADEpro GDT software to present the main findings of the review. We included the outcomes PE, DVT, incidence of bleeding, and incidence of major bleeding in the summary of findings tables. We calculated assumed control intervention risks from the mean number of events in the control groups of the selected studies for each outcome. We used the system developed by the GRADE working group for grading the certainty of the evidence as high, moderate, low and very low, based on within‐study risk of bias, directness of evidence, heterogeneity, precision of effects estimates, and risk of publication bias (Atkins 2004).

Summary of findings 1. IPC plus pharmacological prophylaxis versus IPC alone.

Does combined intermittent pneumatic compression (IPC) plus pharmacological prophylaxis increase prevention of venous thromboembolism compared with IPC alone?
Patient or population: people undergoing surgery or at risk of developing VTE due to surgery, trauma or ICU stay Settings: hospital Intervention: combined modalities ‐ IPC plus pharmacological prophylaxis Comparison: IPC alone
Outcomes	*Anticipated absolute effects ^ (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with IPC alone	Risk with combined modalities	Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
Incidence of PE^a (early postoperative period)	16 per 1000	7 per 1000 (4 to 12)	OR 0.51 (0.29 to 0.91)	5462 (19)	⊕⊕⊝⊝ Low^b
Incidence of DVT^c (early postoperative period)	38 per 1000	20 per 1000 (14 to 28)	OR 0.51 (0.36 to 0.72)	5394 (18)	⊕⊕⊝⊝ Low^b
Incidence of bleeding^d (early postoperative period)	10 per 1000	55 per 1000 (36 to 83)	OR 6.02 (3.88 to 9.35)	4634 (13)	⊕⊝⊝⊝ Very low^e
Incidence of major bleeding^f (early postoperative period)	3 per 1000	19 per 1000 (10 to 39)	OR 5.77 (2.81 to 11.83)	4133 (12)	⊕⊝⊝⊝ Very low^e
* 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;ICU: intensive care unit; IPC: intermittent pneumatic compression; OR: odds ratio; PE: pulmonary embolism; 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.

Date	Event	Description
16 September 2021	New search has been performed	New search run. Twelve new included studies and four new ongoing studies identified.
16 September 2021	New citation required and conclusions have changed	New search run. Twelve new included studies and four new ongoing studies identified. New author joined team. Text updated to reflect new data and current Cochrane recommendations. Conclusions changed.

Date	Event	Description
3 May 2016	New search has been performed	Search updated. Eleven new studies included, nine new studies excluded and three ongoing studies identified.
3 May 2016	New citation required but conclusions have not changed	Search updated. Eleven new studies included, nine new studies excluded and three ongoing studies identified. New author added. Cochrane Risk of bias assessments and 'Summary of findings' table added. Text amended to reflect current Cochrane standards. No change to conclusions.
14 February 2011	Amended	Link to anticoagulant feedback added.
16 June 2008	Amended	Converted to new review format.

Source	Search strategy	Hits retrieved
CENTRAL via CRSO	#1 MESH DESCRIPTOR Thrombosis EXPLODE ALL TREES 4768 #2 MESH DESCRIPTOR Thromboembolism EXPLODE ALL TREES 2058 #3 MESH DESCRIPTOR Venous Thromboembolism EXPLODE ALL TREES 636 #4 MESH DESCRIPTOR Venous Thrombosis EXPLODE ALL TREES 2665 #5 (thrombus* or thrombopro* or thrombotic* or thrombolic* or thromboemboli):TI,AB,KY 6377 #6 MESH DESCRIPTOR Pulmonary Embolism EXPLODE ALL TREES 1006 #7 (DVT or VTE):TI,AB,KY 3624 #8 (blood adj3 clot):TI,AB,KY 5271 #9 (pulmonary adj3 clot):TI,AB,KY 17 #10 (lung adj3 clot):TI,AB,KY 12 #11 MESH DESCRIPTOR Lower Extremity EXPLODE ALL TREES 7078 #12 (((vein or ven) adj thromb)):TI,AB,KY 11181 #13 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 29930 #14 MESH DESCRIPTOR Intermittent Pneumatic Compression Devices EXPLODE ALL TREES 132 #15 MESH DESCRIPTOR Blood Flow Velocity EXPLODE ALL TREES 2421 #16 (((pneumati* or sequential) adj5 compres)):TI,AB,KY 738 #17 ((calf adj4 (inflat or pump* or compres* or squeez))):TI,AB,KY 157 #18 ((foot adj4 (inflat or pump* or compres* or squeez))):TI,AB,KY 107 #19 ((leg adj4 (inflat or pump* or compres* or squeez))):TI,AB,KY 298 #20 (circulat adj3 assist*):TI,AB,KY 49 #21 (a‐v impulse):TI,AB,KY 31 #22 (av impulse):TI,AB,KY 9 #23 (flowtron or revitaleg or presssion or plexipulse):TI,AB,KY 6 #24 #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 3585 #25 #13 AND #24 815 #26 01/01/2016 TO 18/01/2021:CD 858409 #27 #25 AND #26 264	Jan 2021: 264
Clinicaltrials.gov	venous thromboembolism OR Venous Thrombosis OR Pulmonary Embolism \| Intermittent Pneumatic Compression Devices OR Blood Flow Velocity OR av impulse OR sequential compression OR pneumatic compression	Jan 2021: 10
ICTRP Search Portal	venous thromboembolism OR Venous Thrombosis OR Pulmonary Embolism \| Intermittent Pneumatic Compression Devices OR Blood Flow Velocity OR av impulse OR sequential compression OR pneumatic compression	Jan 2021: N/A
MEDLINE (Ovid MEDLINE Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE) 1946 to present	1 Thrombosis/ 2 Thromboembolism/ 3 Venous Thromboembolism/ 4 exp Venous Thrombosis/ 5 (thrombus* or thrombopro* or thrombotic* or thrombolic* or thromboemboli* or thrombos* or embol).ti,ab. 6 exp Pulmonary Embolism/ 7 (DVT or VTE).ti,ab. 8 (blood adj3 clot).ti,ab. 9 (pulmonary adj3 clot).ti,ab. 10 (lung adj3 clot).ti,ab. 11 exp Lower Extremity/bs [Blood Supply] 12 ((vein* or ven) adj thromb).ti,ab. 13 or/1‐12 14 exp Intermittent Pneumatic Compression Devices/ 15 exp Blood Flow Velocity/ 16 ((pneumati* or sequential) adj5 compres).ti,ab. 17 (calf adj4 (inflat or pump* or compres* or squeez)).ti,ab. 18 (foot adj4 (inflat or pump* or compres* or squeez)).ti,ab. 19 (leg adj4 (inflat or pump* or compres* or squeez)).ti,ab. 20 (circulat adj3 assist*).ti,ab. 21 a‐v impulse.ti,ab. 22 av impulse.ti,ab. 23 (flowtron or revitaleg or presssion or plexipulse).ti,ab. 24 or/14‐23 25 13 and 24 26 randomized controlled trial.pt. 27 controlled clinical trial.pt. 28 randomized.ab. 29 placebo.ab. 30 drug therapy.fs. 31 randomly.ab. 32 trial.ab. 33 groups.ab. 34 or/26‐33 35 exp animals/ not humans.sh. 36 34 not 35 37 25 and 36	Jan 2021: 238
Embase	1 thrombosis/ 2 thromboembolism/ 3 venous thromboembolism/ 4 exp vein thrombosis/ 5 (thrombus* or thrombopro* or thrombotic* or thrombolic* or thromboemboli* or thrombos* or embol).ti,ab. 6 exp lung embolism/ 7 (DVT or VTE).ti,ab. 8 (blood adj3 clot).ti,ab. 9 (pulmonary adj3 clot).ti,ab. 10 (lung adj3 clot).ti,ab. 11 ((vein* or ven) adj thromb).ti,ab. 12 or/1‐11 13 exp intermittent pneumatic compression device/ 14 exp blood flow velocity/ 15 ((pneumati* or sequential) adj5 compres).ti,ab. 16 (calf adj4 (inflat or pump* or compres* or squeez)).ti,ab. 17 (foot adj4 (inflat or pump* or compres* or squeez)).ti,ab. 18 (leg adj4 (inflat or pump* or compres* or squeez)).ti,ab. 19 (circulat adj3 assist*).ti,ab. 20 a‐v impulse.ti,ab. 21 av impulse.ti,ab. 22 (flowtron or revitaleg or presssion or plexipulse).ti,ab. 23 or/13‐22 24 12 and 23 25 randomized controlled trial/ 26 controlled clinical trial/ 27 random$.ti,ab. 28 randomization/ 29 intermethod comparison/ 30 placebo.ti,ab. 31 (compare or compared or comparison).ti. 32 ((evaluated or evaluate or evaluating or assessed or assess) and (compare or compared or comparing or comparison)).ab. 33 (open adj label).ti,ab. 34 ((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab. 35 double blind procedure/ 36 parallel group$1.ti,ab. 37 (crossover or cross over).ti,ab. 38 ((assign$ 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. 39 (assigned or allocated).ti,ab. 40 (controlled adj7 (study or design or trial)).ti,ab. 41 (volunteer or volunteers).ti,ab. 42 trial.ti. 43 or/25‐42 44 24 and 43	Jan 2021: 392
CINAHL	S38 S24 AND S37 S37 S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33 OR S34 OR S35 OR S36 S36 MH "Random Assignment" S35 MH "Single‐Blind Studies" or MH "Double‐Blind Studies" or MH "Triple‐Blind Studies" S34 MH "Crossover Design" S33 MH "Factorial Design" S32 MH "Placebos" S31 MH "Clinical Trials" S30 TX "multi‐centre study" OR "multi‐center study" OR "multicentre study" OR "multicenter study" OR "multi‐site study" S29 TX crossover OR "cross‐over" S28 AB placebo* S27 TX random* S26 TX trial* S25 TX "latin square" S24 S13 AND S23 S23 S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 S22 TX flowtron or revitaleg or presssion or plexipulse S21 TX av impulse S20 TX a‐v impulse S19 TX circulat* n3 assist* S18 TX leg n4 (inflat* or pump* or compres* or squeez) S17 TX foot n4 (inflat or pump* or compres* or squeez) S16 TX calf n4 (inflat or pump* or compres* or squeez) S15 TX (pneumati or sequential) n5 compres* S14 (MH "Blood Flow Velocity") S13 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 S12 TX (vein* or ven) n thromb S11 (MH "Lower Extremity+/BS") S10 TX lung n3 clot* S9 TX pulmonary n3 clot* S8 TX blood n3 clot* S7 TX DVT or VTE S6 (MH "Pulmonary Embolism") S5 TX thrombus* or thrombopro* or thrombotic* or thrombolic* or thromboemboli* or thrombos* or embol* S4 (MH "Venous Thrombosis+") S3 (MH "Venous Thromboembolism") S2 (MH "Thromboembolism") S1 (MH "Thrombosis")	Jan 2021: 71

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Incidence of PE ‐ orthopaedic and non‐orthopaedic patients	19	5462	Odds Ratio (M‐H, Fixed, 95% CI)	0.51 [0.29, 0.91]
1.1.1 Orthopaedic patients	3	445	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.1.2 Non‐orthopaedic patients	16	5017	Odds Ratio (M‐H, Fixed, 95% CI)	0.51 [0.29, 0.91]
1.2 Incidence of PE ‐ foot IPC or other IPC	19	5462	Odds Ratio (M‐H, Fixed, 95% CI)	0.51 [0.29, 0.91]
1.2.1 Foot IPC	1	50	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.2.2 Other IPC	18	5412	Odds Ratio (M‐H, Fixed, 95% CI)	0.51 [0.29, 0.91]
1.3 Incidence of DVT ‐ orthopaedic and non‐orthopaedic patients	18	5394	Odds Ratio (M‐H, Fixed, 95% CI)	0.51 [0.36, 0.72]
1.3.1 Orthopaedic patients	3	445	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.38, 1.69]
1.3.2 Non‐orthopaedic patients	15	4949	Odds Ratio (M‐H, Fixed, 95% CI)	0.46 [0.31, 0.68]
1.4 Incidence of symptomatic DVT ‐ orthopaedic and non‐orthopaedic patients	10	4089	Odds Ratio (M‐H, Fixed, 95% CI)	0.48 [0.21, 1.10]
1.4.1 Orthopaedic patients	1	250	Odds Ratio (M‐H, Fixed, 95% CI)	1.50 [0.06, 37.33]
1.4.2 Non‐orthopaedic patients	9	3839	Odds Ratio (M‐H, Fixed, 95% CI)	0.44 [0.19, 1.04]
1.5 Incidence of DVT ‐ by foot IPC or other IPC	18	5395	Odds Ratio (M‐H, Fixed, 95% CI)	0.51 [0.36, 0.72]
1.5.1 Foot IPC	1	50	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.5.2 Other IPC	17	5345	Odds Ratio (M‐H, Fixed, 95% CI)	0.51 [0.36, 0.72]
1.6 Incidence of bleeding ‐ orthopaedic and non‐orthopaedic patients	13	4634	Odds Ratio (M‐H, Fixed, 95% CI)	6.02 [3.88, 9.35]
1.6.1 Orthopaedic patients	2	400	Odds Ratio (M‐H, Fixed, 95% CI)	2.79 [0.77, 10.18]
1.6.2 Non‐orthopaedic patients	11	4234	Odds Ratio (M‐H, Fixed, 95% CI)	6.61 [4.14, 10.56]
1.7 Incidence of major bleeding ‐ orthopaedic and non‐orthopaedic patients	12	4133	Odds Ratio (M‐H, Fixed, 95% CI)	5.77 [2.81, 11.83]
1.7.1 Orthopaedic patients	2	400	Odds Ratio (M‐H, Fixed, 95% CI)	3.35 [0.13, 83.62]
1.7.2 Non‐orthopaedic patients	10	3733	Odds Ratio (M‐H, Fixed, 95% CI)	5.91 [2.83, 12.36]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Incidence of PE ‐ orthopaedic and non‐orthopaedic patients	15	6737	Odds Ratio (M‐H, Fixed, 95% CI)	0.46 [0.30, 0.71]
2.1.1 Orthopaedic patients	8	1202	Odds Ratio (M‐H, Fixed, 95% CI)	0.58 [0.08, 4.49]
2.1.2 Non‐orthopaedic patients	7	5535	Odds Ratio (M‐H, Fixed, 95% CI)	0.46 [0.29, 0.71]
2.2 Incidence of PE ‐ foot IPC or other IPC	15	6737	Odds Ratio (M‐H, Fixed, 95% CI)	0.46 [0.30, 0.71]
2.2.1 Foot IPC	4	324	Odds Ratio (M‐H, Fixed, 95% CI)	0.32 [0.01, 8.25]
2.2.2 Other IPC	11	6413	Odds Ratio (M‐H, Fixed, 95% CI)	0.47 [0.30, 0.72]
2.3 Incidence of DVT ‐ orthopaedic and non‐orthopaedic patients	17	6151	Odds Ratio (M‐H, Random, 95% CI)	0.38 [0.21, 0.70]
2.3.1 Orthopaedic patients	10	3075	Odds Ratio (M‐H, Random, 95% CI)	0.34 [0.18, 0.68]
2.3.2 Non‐orthopaedic patients	7	3076	Odds Ratio (M‐H, Random, 95% CI)	0.46 [0.13, 1.61]
2.4 Incidence of symptomatic DVT ‐ orthopaedic and non‐orthopaedic patients	7	3032	Odds Ratio (M‐H, Fixed, 95% CI)	0.83 [0.34, 2.01]
2.4.1 Orthopaedic patients	3	477	Odds Ratio (M‐H, Fixed, 95% CI)	2.09 [0.38, 11.50]
2.4.2 Non‐orthopaedic patients	4	2555	Odds Ratio (M‐H, Fixed, 95% CI)	0.55 [0.18, 1.66]
2.5 Incidence of DVT ‐ foot IPC or other IPC	16	4148	Odds Ratio (M‐H, Random, 95% CI)	0.34 [0.18, 0.63]
2.5.1 Foot IPC	4	324	Odds Ratio (M‐H, Random, 95% CI)	0.40 [0.05, 3.47]
2.5.2 Other IPC	12	3824	Odds Ratio (M‐H, Random, 95% CI)	0.31 [0.17, 0.54]
2.6 Incidence of bleeding ‐ orthopaedic and non‐orthopaedic patients	6	1314	Odds Ratio (M‐H, Fixed, 95% CI)	0.87 [0.56, 1.35]
2.6.1 Orthopaedic patients	3	550	Odds Ratio (M‐H, Fixed, 95% CI)	0.64 [0.20, 2.07]
2.6.2 Non‐orthopaedic patients	3	764	Odds Ratio (M‐H, Fixed, 95% CI)	0.91 [0.57, 1.47]
2.7 Incidence of major bleeding ‐ orthopaedic and non‐orthopaedic patients	5	908	Odds Ratio (M‐H, Fixed, 95% CI)	1.21 [0.35, 4.18]
2.7.1 Orthopaedic patients	3	551	Odds Ratio (M‐H, Fixed, 95% CI)	1.07 [0.21, 5.54]
2.7.2 Non‐orthopaedic patients	2	357	Odds Ratio (M‐H, Fixed, 95% CI)	1.42 [0.21, 9.49]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Incidence of PE	3	605	Odds Ratio (M‐H, Fixed, 95% CI)	0.33 [0.03, 3.19]
3.2 Incidence of DVT	3	605	Odds Ratio (M‐H, Fixed, 95% CI)	0.83 [0.48, 1.42]
3.3 Incidence of symptomatic DVT	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.4 Incidence of bleeding	3	616	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [0.27, 5.53]
3.5 Incidence of major bleeding	3	616	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.15, 4.17]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Incidence of PE	13	4159	Odds Ratio (M‐H, Fixed, 95% CI)	0.54 [0.28, 1.07]
4.2 Incidence of DVT	13	4159	Odds Ratio (M‐H, Fixed, 95% CI)	0.53 [0.36, 0.77]
4.3 Incidence of symptomatic DVT	7	3064	Odds Ratio (M‐H, Fixed, 95% CI)	1.21 [0.15, 9.63]
4.4 Incidence of DVT by foot IPC or other IPC	17	5085	Odds Ratio (M‐H, Fixed, 95% CI)	0.52 [0.36, 0.74]
4.4.1 Foot IPC	1	50	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.4.2 Other IPC	16	5035	Odds Ratio (M‐H, Fixed, 95% CI)	0.52 [0.36, 0.74]
4.5 Incidence of bleeding	10	4120	Odds Ratio (M‐H, Fixed, 95% CI)	5.45 [3.38, 8.80]
4.6 Incidence of major bleeding	9	3619	Odds Ratio (M‐H, Fixed, 95% CI)	5.90 [2.82, 12.33]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Incidence of PE	11	5758	Odds Ratio (M‐H, Fixed, 95% CI)	0.45 [0.29, 0.70]
5.2 Incidence of DVT	13	5172	Odds Ratio (M‐H, Random, 95% CI)	0.44 [0.22, 0.87]
5.3 Incidence of symptomatic DVT	5	2312	Odds Ratio (M‐H, Fixed, 95% CI)	1.02 [0.29, 3.54]
5.4 Incidence of DVT by foot IPC or other IPC	15	5431	Odds Ratio (M‐H, Random, 95% CI)	0.42 [0.23, 0.80]
5.4.1 Foot IPC	4	324	Odds Ratio (M‐H, Random, 95% CI)	0.40 [0.05, 3.47]
5.4.2 Other IPC	11	5107	Odds Ratio (M‐H, Random, 95% CI)	0.40 [0.20, 0.81]
5.5 Incidence of bleeding	4	594	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.30, 2.14]
5.6 Incidence of major bleeding	4	595	Odds Ratio (M‐H, Fixed, 95% CI)	1.21 [0.35, 4.18]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Incidence of PE	2	405	Odds Ratio (M‐H, Fixed, 95% CI)	0.33 [0.03, 3.19]
6.2 Incidence of DVT	2	405	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.44, 1.39]

*Study characteristics*
Methods	Study design: RCT Method of randomisation: centralised computer‐generated randomisation system with variable block size. Randomisation was stratified according to study site and type of heparin used Concealment of allocation: centralised computer‐generated randomisation system with variable block size Exclusions: 1 site was terminated by the study sponsor because some participants had been enrolled without full adherence to the approved informed‐consent process, and all data from this site were excluded from the analyses Losses to follow‐up: none ITT analysis: yes, modified
Participants	Countries: Saudi Arabia, Canada, Australia, and India Number of participants: 2003, intervention group 991; control group 1012 Age (mean, years): intervention group 57.6; control group 58.7 Sex: 1148 (57.3%) male Inclusion criteria: medical‐surgical ICU patients ≥ 14 years old at participating ICUs. ICUs that use other age cut‐off for adult patients will adhere to their local standard (16 or 18 years); patient weight ≥ 45 kg; expected ICU LOS ≥ 72 h; eligible for pharmacologic thromboprophylaxis with UFH and LMWH Exclusion criteria: patient treated with IPC for > 24 h in this current ICU admission; patient in the ICU for > 48 h; patient treated with pharmacologic VTE prophylaxis with medications other than UFH or LMWH; inability or contraindication to applying IPC to both legs (burns in the lower extremities, lacerations, active skin infection and ischaemic lower limb at the site of IPC placement, acute ischaemia in the lower extremities, amputated foot or leg on 1 or both sides, compartment syndrome, severe PAD, vein ligation, gangrene, recent vein grafts and draining incisions, evidence of bone fracture in lower extremities); therapeutic dose of anticoagulation with UFH or LMWH; pregnancy; limitation of life support; life expectancy ≤ 7 days or palliative care; allergy to the sleeve material; patients with inferior VCF
Interventions	Intervention group: IPC and heparin (any type) Control group: heparin (any type)
Outcomes	Primary outcome: incident (i.e. new) proximal lower‐limb DVT, as detected on twice‐weekly lower‐limb US after the third calendar day since randomisation until ICU discharge, death, attainment of full mobility, or study day 28, whichever occurred first. DVT that were detected on study days 1 to 3 were considered to be prevalent (i.e. pre‐existing) and were not included in the primary outcome analysis Secondary outcomes: percentage of participants who had prevalent proximal DVT, the occurrence of any lower limb DVT thromboses (proximal, distal, prevalent, or incident), the occurrence of PE, a composite outcome of VTE that included PE or all prevalent and incident lower‐limb DVT, a composite outcome of VTE or death from any cause at 28 days, and safety outcomes
Funding	Grants from King Abdulaziz City for Science and Technology (AT 34‐65) and King Abdullah International Medical Research Center (RC12/045/R)
Declarations of interest	MH reports receiving payment for patient cost, US and start‐up fees
Notes	The modified ITT population comprised all the participants who underwent randomisation with the exception of those who withdrew consent for both the intervention and the collection of data and those who were identified as ineligible after randomisation. The single case of fatal PE was observed in the control group (personal communication).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation system
Allocation concealment (selection bias)	Low risk	Centralised computer‐generated randomisation system with variable block size
Blinding of participants and personnel (performance bias) All outcomes	High risk	No placebo IPC was used
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Unclear if outcome assessors of adjudicating committee (if any) were blinded to allocation group, with the exception of radiologists who interpreted US findings
Incomplete outcome data (attrition bias) All outcomes	Low risk	Relatively few exclusions
Selective reporting (reporting bias)	Low risk	None detected
Other bias	Low risk	None detected

*Study characteristics*
Methods	Study design: CCT Method of randomisation: study was planned to be randomised and method of planned randomisation was stated as patient order Concealment of allocation: none stated Exclusions: none Losses to follow‐up: none ITT analysis: yes
Participants	Country: USA Number of participants: 68, intervention group 32; control group 36 Age (mean, years): intervention group 67; control group 65 Sex: male Inclusion criteria: retropubic RP with bilateral pelvic prostatectomy for clinically localised prostate cancer Exclusion criteria: none stated
Interventions	Intervention group: SCDs with elastic stockings and UFH (5000 IU twice daily, sc) Control group: SCDs with elastic stockings
Outcomes	Symptomatic PE, confirmed with ventilation‐perfusion scan
Funding	Not reported
Declarations of interest	Not reported
Notes	The study was planned to be randomised but due to administrative errors the randomisation protocol was violated SCDs were started in the operating room and discontinued when the participants were ambulatory, usually 18 h postoperatively Heparin was started 2 h before the operation and was continued for 7 days or the time of discharge Study was discontinued because of bleeding complications associated with heparin use. No specific bleeding definitions were provided.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	The study was planned to be randomised but due to administrative errors the randomisation protocol was violated. Method of planned randomisations was stated as patient order
Allocation concealment (selection bias)	High risk	Alternating patients received the study medication and in most cases the surgeon was aware of which participants received heparin
Blinding of participants and personnel (performance bias) All outcomes	High risk	In most cases the surgeon was aware of which participants received heparin, and the same perhaps applies to the anaesthesia personnel
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	It is unclear if the personnel performing the pulmonary ventilation‐perfusion scans or angiograms were aware of which participants received heparin
Incomplete outcome data (attrition bias) All outcomes	Low risk	No participants were lost to follow‐up
Selective reporting (reporting bias)	Low risk	PE was the only VTE event stated in methodology and was reported
Other bias	Unclear risk	No baseline characteristics, apart from age, were provided

*Study characteristics*
Methods	Study design: quasi‐RCT Method of randomisation: by the last digit of year of birth Concealment of allocation: none Exclusions: not reported Losses to follow‐up: not reported ITT analysis: yes
Participants	Country: Turkey Number of participants: 80 Age (mean, years): not provided Sex: not provided Inclusion criteria: trauma patients, at high risk for bleeding Exclusion criteria: low risk for bleeding
Interventions	Intervention group: LMWH (40 mg/day) combined with IPC Control group: IPC
Outcomes	DVT on DUS and clinically evident DVT; and PE by CT scanning
Funding	Not reported
Declarations of interest	Not reported
Notes	Information on randomisation and blinding was obtained from the study authors. No information on start and discontinuation of IPC or LMWH
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Quasi‐randomised trial, randomised by the last digit of year of birth
Allocation concealment (selection bias)	High risk	Quasi‐randomised trial so predictable
Blinding of participants and personnel (performance bias) All outcomes	High risk	No placebo anticoagulants were used
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The radiologist who performed the US tests was not aware of participant allocation
Incomplete outcome data (attrition bias) All outcomes	Low risk	All study participants were reported in the results section
Selective reporting (reporting bias)	Low risk	DVT and PE were the VTE events stated in methodology and results were provided
Other bias	Unclear risk	Insufficient details were provided to allow a conclusion to be made

*Study characteristics*
Methods	Study design: RCT  Method of randomisation: table of random numbers Concealment of allocation: not reported Exclusions post randomisation: intervention group 57; control group 178 Losses to follow‐up: yes ITT analysis: no
Participants	Country: USA Number of participants: randomised 2786, completed 2551 Age (mean, years): 63.9 Sex: male 1782; female 769 Inclusion criteria: open heart surgery Exclusion criteria: known prior DVT; bleeding complications; intraoperative death; intolerance to IPC; or withdrawal of prophylaxis before full ambulation
Interventions	Intervention group: UFH (5000 IU twice daily, sc) and SCDs Control group: UFH (5000 IU twice daily, sc)
Outcomes	Symptomatic PE, confirmed by ventilation perfusion scan and/or pulmonary angiography
Funding	Not reported
Declarations of interest	Not reported
Notes	Both prophylactic methods were started immediately after surgery and continued for 4‐5 days or until participants were fully ambulatory
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A table of random numbers was used
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	High risk	No placebo device was used
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	It is unclear if the personnel performing the pulmonary ventilation‐perfusion scans or angiograms were aware of which participants used a compression device
Incomplete outcome data (attrition bias) All outcomes	High risk	A large number of participants were excluded after randomisation
Selective reporting (reporting bias)	Low risk	PE was the only VTE event stated in methodology and was reported
Other bias	Low risk	Baseline characteristics were comparable

*Study characteristics*
Methods	Study design: quasi‐randomised trial Method of randomisation: "..consecutive random numbers were selected from a random number table, assigned to each patient, and then divided by four. When the remainder was 0, 1, 2, and 3, the patient was allocated to groups A, B, C, and D, respectively. The patients were included sequentially according to the date of surgery." Concealment of allocation: the patients were included sequentially according to the date of surgery Exclusions: none stated Losses to follow‐up: none stated ITT analysis: yes
Participants	Country: China Number of participants: 477, intervention group 162; control group 1 (LMWH, 162); control group 2 (IPC, 153). Excluding 159 patients receiving only elastic stockings Age (mean, years): intervention group 53.3; control group 1 54.7; control group 2 52.6 Sex: 477 (100%) female Inclusion criteria: age >18 years; carrying ≥ 1 risk factor for postoperative VTE; not taking any prophylactic measures before enrolment; willing to sign a written informed consent form; gynaecologic diseases may be malignant or benign (malignant diseases included malignancies of the ovary, uterine body, uterine cervix, vulva, and other parts of the pelvis; benign diseases included uterine myoma, uterine adenomyoma, ovarian benign tumours, pelvic floor prolapsed, and others such as hydrosalpinx, fallopian tube abscess, encapsulated effusion, and mesosalpinx cyst) Exclusion criteria: preoperative thrombophlebitis or PE; preoperative acute lower extremity venous thrombosis; preoperative thrombocytopenia (PLT count < 100×10⁹/L) or coagulation disorders; usage of anticoagulant drugs such as aspirin within 1 month; bleeding tendency as revealed by coagulation indexes or previous intracranial or gastrointestinal bleeding; congestive heart failure or pulmonary oedema; serious leg abnormalities (such as dermatitis, gangrene, or recent skin grafting), severe lower limb vascular atherosclerosis, lower limb ischaemic vascular disease, or severe leg deformity; imperception of dorsalis pedis artery pulse
Interventions	Intervention group: IPC with elastic stockings and LMWH dalteparin Control group 1: dalteparin with elastic stockings Control group 2: IPC with elastic stockings
Outcomes	Screening of VTE was performed within 7 days before and 3–5 days after surgery. Initially, colour DUS imaging of lower extremities was performed by an experienced professional using an LEGIQ E9 colour Doppler system with the probe frequency set at 8.4–9 MHz. If VTE was found or suspected, lower limb venography was performed to confirm the presence of DVT, and CTPA was performed to detect if PE was present. Bleeding events, classified as major and minor haemorrhagic events
Funding	The Capital Health Research and Development of Special Project (No. 2011‐2003‐03)
Declarations of interest	None
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Quote: "A simple randomization method was adopted for this study. Based on the calculated sample size (see below), 660 consecutive random numbers were selected from a random number table, assigned to each patient, and then divided by four. When the remainder was 0, 1, 2, and 3, the patient was allocated to groups A, B, C, and D, respectively. The patients were included sequentially according to the date of surgery."
Allocation concealment (selection bias)	High risk	The patients were included sequentially according to the date of surgery
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study without use of placebo
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label study without use of placebo
Incomplete outcome data (attrition bias) All outcomes	Low risk	No attrition
Selective reporting (reporting bias)	Low risk	Results provided for all outcomes
Other bias	Low risk	None detected

*Study characteristics*
Methods	Study design: randomised, double‐blind, placebo‐controlled, superiority trial Method of randomisation: centralised computer‐generated schedule (1:1 randomisation in blocks of 4 and stratified by centre) Concealment of allocation: yes Exclusions post‐randomisation: 24 Losses to follow‐up: none ITT analysis: no
Participants	Country: USA Number of participants: 1309 randomised, 1285 randomised and treated Age: median age 59 and 60 years in the control and treatment groups, respectively Sex: male 635; female 650 Inclusion criteria: abdominal surgery expected to last > 45 min in patients aged over 40 years; or patients weighing > 50 kg Exclusion criteria: vascular surgery with evidence of leg ischaemia caused by peripheral vascular disease; unable to receive IPC or elastic stockings; pregnant women and women of childbearing age not using effective contraception; life‐expectancy < 6 months; clinical signs of DVT and/or history of VTE within the previous 3 months; active bleeding; documented congenital or acquired bleeding disorder; active ulcerative GI disease (unless it was the reason for the present surgery); haemorrhagic stroke or surgery on the brain, spine or eyes within the previous 3 months; bacterial endocarditis or other contraindications for anticoagulant therapy; planned indwelling intrathecal or epidural catheter for > 6 h after surgical closure; unusual difficulty in achieving epidural or spinal anaesthesia; known hypersensitivity to fondaparinux or iodinated contrast medium; current addictive disorders; serum creatinine concentration > 2.0 mg/dL in a well‐hydrated patient; PLT count below 100,000 mm; or patients requiring anticoagulant therapy or other pharmacologic prophylaxis besides IPC
Interventions	Intervention group: IPC and fondaparinux  Control group: IPC
Outcomes	VTE (defined as DVT detected by mandatory screening and/or documented symptomatic DVT or PE, or both) and individual components up to day 10. Symptomatic VTE up to day 10 and day 32 Major bleeding (defined as bleeding that was fatal, retroperitoneal, intracranial, or involved any other critical organ, led to intervention being discontinued, or was associated with a bleeding index of ≥ 2.0) detected during the treatment period Death during the treatment period and up to day 32
Funding	Sanofi‐Synthélabo and GlaxoSmithKline
Declarations of interest	Not reported
Notes	Study medications were packaged in boxes of identical appearance Of the 1309 randomised participants, 842 (64.3%) had an evaluable venogram performed and were included in the primary efficacy analysis Major bleeding occurred in 10 participants (1.6%) and 1 participant (0.2%) of the intervention and control groups, respectively (P = 0.006) During the on‐study‐drug period of 5–9 days, all participants were to receive VTE prophylaxis with IPC using any type of device, except a foot pump, for a duration left to the investigator's discretion. The first injection of fondaparinux or placebo was scheduled 6–8 h after surgical closure, provided that haemostasis was achieved. The duration of the on‐study‐drug period was 5–9 days. If the participant was discharged from hospital before completing the on‐study‐drug period, a visiting nurse administered the remaining study injections
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Centralised computer‐generated schedule randomisation (1:1 randomisation in blocks of four and stratified by centre)
Allocation concealment (selection bias)	Low risk	Centralised computer‐generated schedule randomisation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Use of placebo injections
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Reports double‐blind (use of placebo injections) but it is unclear if the personnel performing diagnostic testing were aware of participant allocation
Incomplete outcome data (attrition bias) All outcomes	High risk	A large number of exclusions in both study arms, around 35% of the total number of participants, mainly because of lack of mandatory or interpretable venography
Selective reporting (reporting bias)	Low risk	DVT and PE were the primary efficacy outcomes and they were reported in the results
Other bias	Low risk	Demographic variables and risk factors at baseline, type of anaesthesia, and type and duration of surgery were similar in the 2 groups among both randomised and treated participants (Tables 1 and 2) and among participants analysed for primary efficacy

Study	Reason for exclusion
Ailawadi 2001	Retrospective case‐control study
Eskander 1997	Use of combined modalities was not concurrent in the intervention group
Frim 1992	Controlled before and after study
Gagner 2012	Registry study, non‐randomised
Gelfer 2006	Pharmacological prophylaxis was not the same in the 2 study groups
Kamran 1998	Controlled before and after study
Kiudelis 2010	Investigation restricted to intraoperative period up to 10 min after extubation
Kumaran 2008	The control (single modality) group included participants who were allocated to heparin or pneumatic compression
Lieberman 1994	Pharmacological prophylaxis consisted of aspirin, which has limited thromboprophylactic properties
Macdonald 2003	Pharmacological prophylaxis was not the same in the 2 study groups
Mehta 2010	Only aggregated VTE rates and not separate DVT and PE rates were provided and the study authors did not reply when we requested individual data
Nathan 2006	Prospective case‐control study
Patel 2010	Retrospective study
Roberts 1975	Pneumatic compression was used only intraoperatively
Spinal cord injury investigators	Pharmacological prophylaxis was not the same in the 2 study groups
Stannard 2006	Use of enoxaparin was not concurrent in the 2 study groups
Tsutsumi 2000	Controlled before and after study
Wan 2015	Retrospective study
Westrich 1996	Pharmacological prophylaxis consisted of aspirin, which has limited thromboprophylactic properties
Whitworth 2011	Retrospective case‐control study investigating preoperative anticoagulation in patients on postoperative LMWH and SCDs
Winemiller 1999	Retrospective case‐control study

Study name	ChiCTR1800014257
Methods	Multicenter parallel RCT
Participants	Women undergoing gynaecologic pelvic surgery
Interventions	High‐risk patients: GCS (control group) vs GCS + LMWH Very high‐risk patients: GCS+ IPC (control group) vs GCS + IPC + LMWH
Outcomes	Lower extremity venous DUS findings, haematology laboratory measures and CTPA findings
Starting date	1 January 2018
Contact information	Zhengyu Zhang
Notes

Study name	EUCTR2007‐006206‐24
Methods	IPC with and without early anticoagulant treatment
Participants	Patients with acute primary intracerebral haemorrhage
Interventions	Blind randomised trial of IPC with and without early anticoagulant treatment
Outcomes	Not provided
Starting date	17 December 2008
Contact information	Not provided
Notes	Study ended on 30 June 2016, no results are available

Study name	NCT00740987 (CIREA 2)
Methods	RCT in ICU patients without high risk of bleeding
Participants	621 ICU patients
Interventions	Patients were randomised to use IPC or not
Outcomes	Primary outcome measures: combined criterion evaluated at day 6 ± 2 days after randomisation: symptomatic VTE event, non‐fatal, objectively confirmed; death related to PE; asymptomatic DVT of the lower limbs detected by CUS on day 6 (time frame: 6 ± 2 days) Secondary outcome measures: symptomatic thromboembolic events occurred between day 6 and day 90; total mortality evaluated at 1 month and 3 months (time frame: 6 days to 3 months)
Starting date	October 2007
Contact information	Karine Lacut, MD. CHU Brest France, Univ Brest, EA 3878
Notes	Study completed in January 2015, with no results being presented or published at the time of writing this review

Study name	NCT02271399
Methods	Double‐blind, parallel group, RCT
Participants	Patients undergoing TKA
Interventions	Aspirin and IPC vs rivaroxaban and IPC
Outcomes	VTE, bleeding
Starting date	October 2014
Contact information	Jin Kyu Lee
Notes	Competed on February 2016, no results have been published

PERMALINK

Combined intermittent pneumatic leg compression and pharmacological prophylaxis for prevention of venous thromboembolism

Stavros Kakkos

George Kirkilesis

Joseph A Caprini

George Geroulakos

Andrew Nicolaides

Gerard Stansby

Daniel J Reddy

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Summary of findings 1. IPC plus pharmacological prophylaxis versus IPC alone.

Summary of findings 2. IPC plus pharmacological prophylaxis versus pharmacological prophylaxis alone.

Results

Description of studies

Results of the search

1.

Included studies

Excluded studies

Ongoing studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Intermittent pneumatic leg compression (IPC) plus pharmacological prophylaxis versus IPC alone

1.1. Analysis.

1.2. Analysis.

1.3. Analysis.

1.4. Analysis.

1.5. Analysis.

1.6. Analysis.

1.7. Analysis.

Intermittent pneumatic leg compression (IPC) plus pharmacological prophylaxis versus pharmacological prophylaxis alone

2.1. Analysis.

2.2. Analysis.

2.3. Analysis.

2.4. Analysis.

Study name	NCT03559114 (PROTEST)
Methods	Phase III, multi‐centre, double blind, RCT
Participants	Patients with traumatic brain Injury
Interventions	SCD versus SCS and dalteparin
Outcomes	Clinically important VTE, clinically‐important intracranial bleeding progression, objectively confirmed new or progressing intracranial bleeding on radiology, mortality at 7 days, 30 days, 180 days, delayed VTE after day 7, functional neurological outcome at day 30 as measured by Glasgow Outcome Scale Extended, functional neurological outcome at day 180 as measured by Glasgow Outcome Scale Extended, quality of life outcome at 30 days as measured by the EuroQol5D, quality of life outcome at 180 days as measured by the EuroQol5D
Starting date	19 July 2018
Contact information	Farhad Pirouzmand, MD, MSc, FRCSC
Notes