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

Stavros K Kakkos; Joseph A Caprini; George Geroulakos; Andrew N Nicolaides; Gerard Stansby; Daniel J Reddy; Ioannis Ntouvas

doi:10.1002/14651858.CD005258.pub3

. 2016 Sep 7;2016(9):CD005258. doi: 10.1002/14651858.CD005258.pub3

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

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

Editor: Cochrane Vascular Group

PMCID: PMC6457599 PMID: 27600864

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 an 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 versus single modalities in preventing venous thromboembolism.

Search methods

Selection criteria

Randomized controlled trials (RCTs) or controlled clinical trials (CCTs) of combined IPC and pharmacological interventions used to prevent VTE.

Data collection and analysis

We independently selected trials and extracted data. Disagreements were resolved 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.

Main results

We included a total of 22 trials (9137 participants) of which 15 were randomized trials (7762 participants). The overall risk of bias was mostly unclear or high due to selection and performance bias. We used GRADE to assess the quality of the evidence and this was downgraded from high to moderate or very low due to the risk of bias, imprecision or indirectness.

The rate of PE in the studies comparing IPC alone with combined IPC and pharmacological prophylaxis was low, underpowering the analyses. The incidence of symptomatic PE was 0.79% with IPC, but ranged between 0.1 to 1% with combined IPC and pharmacological prophylaxis (OR 0.49, 95% CI 0.18 to 1.34; 12 studies, 3017 participants, moderate quality evidence). The incidence of DVT was 4.10% in the IPC group and 2.19% in the combined group showing a reduced incidence of DVT in favour of the combined group (OR 0.52, 95% CI 0.33 to 0.82; 11 studies, 2934 participants, moderate quality evidence). The addition of an anticoagulant to IPC, however, increased the risk of any bleeding compared to IPC alone; 0.66% (7/1053) in the IPC group and 4.0% (44/1102) in the combined group (OR 5.04, 95% CI 2.36 to 10.77; 7 studies, 2155 participants, moderate quality evidence). Major bleeding followed a similar pattern; 0.1% (1/1053) in the IPC group to 1.5% (17/1102) in the combined group (OR 6.81, 95% CI 1.99 to 23.28; 7 studies, 2155 participants, moderate quality evidence).

We detected no difference between the type of surgery subgroups such as orthopedic and non‐orthopedic participants for DVT incidence (P = 0.16). Tests for differences between type of surgery subgroups were not possible for PE incidence.

Compared with pharmacological prophylaxis alone, the use of combined IPC and pharmacological prophylaxis modalities reduced the incidence of symptomatic PE from 2.92% to 1.20% (OR 0.39, 95% CI 0.23 to 0.64; 10 studies, 3544 participants, moderate quality evidence). The incidence of DVT was 6.2% in the pharmacological prophylaxis group and 2.9% in the combined group showing no difference between the combined and pharmacological prophylaxis groups (OR 0.42, 95% CI 0.18 to 1.03; 11 studies, 2866 participants, moderate quality evidence). Increased bleeding side effects were not observed for IPC when it was added to anticoagulation (bleeding: OR 0.80, 95% CI 0.30 to 2.14, very low quality evidence; major bleeding: OR 1.21, 95% CI 0.35 to 4.18, very low quality evidence, 3 studies, 244 participants).

No difference was detected between the type of surgery subgroups for PE incidence (P = 0.68) or for DVT incidence (P = 0.10).

Authors' conclusions

Moderate quality evidence suggests that combining IPC and pharmacological prophylaxis, compared with IPC or pharmacological prophylaxis alone, decreases the incidence of DVT when compared to compression, and incidence of PE when compared to anticoagulation. Moderate quality evidence suggests that there is no difference between combined and single modalities in the incidence of PE when compared with compression alone and DVT when compared with anticoagulation alone. The quality of evidence for PE or DVT was downgraded to moderate due to imprecision or risk of bias in study methodology, highlighting the need for further research. Moderate quality evidence suggests the addition of pharmacological prophylaxis to IPC, increased the risk of bleeding compared to IPC alone, a side effect not observed for IPC when added to pharmacological prophylaxis (very low quality evidence), as expected for a physical method of thromboprophylaxis. The quality of evidence for bleeding was downgraded to moderate due to indirectness or very low due to risk of bias in study methodology, indirectness and imprecision highlighting the need for further research. Nevertheless, the results of the current review agree with current guideline recommendations, which support the use of combined modalities in hospitalised patients (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.

Plain language summary

Combined intermittent pneumatic leg compression and medication for the prevention of deep vein thrombosis and pulmonary embolism

Background

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are collectively known as venous thromboembolism (VTE), and occur when a blood clot develops inside the leg veins (DVT) and travels to the lungs (PE). They are possible complications of hospitalisation resulting from surgery or trauma. These complications extend hospital stay and are associated with long‐term disability and death. Patients undergoing total hip or knee replacement surgery or surgery for colorectal cancer are at high risk of venous thromboembolism. Sluggish venous blood flow, increased blood clotting and blood vessel wall injury are contributing factors. Treating more than one of these causes may improve prevention. Mechanical intermittent pneumatic leg compression (IPC) reduces sluggish blood flow (venous stasis) while medications such as aspirin and anticoagulants (low molecular weight heparin) 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. This review is an update of a review first published in 2008.

Study characteristics and key results

We identified 22 trials with a total of 9137 participants to include in this review (current until May 2016). The mean age of participants, where reported, was 65.2 years. Most participants had either a high‐risk procedure or condition. The predisposing conditions were orthopedic surgery in 12 studies and urology, cardiothoracic, neurosurgery, trauma, general surgery, gynaecology or other types of participants in the remaining studies.

Compared to IPC alone, IPC plus medication did not show differences in the incidence (rate of new cases) of PE (12 studies with a total of 3017 participants). The incidence of DVT was reduced for IPC combined with medication when compared with IPC alone (11 studies with a total of 2934 participants). The addition of a medication to IPC, however, increased the risk for any bleeding compared to IPC alone, from 0.66% to 4.0%. Major bleeding followed a similar pattern, with an increase from 0.1% to 1.5%.Further analysis looking at different subgroups of participants (orthopedic and non‐orthopedic participants) did not show any overall difference in DVT while it was not possible to assess differences between subgroups for PE.

Compared with medication alone, combined IPC and medication reduced the incidence of PE (10 studies with 3544 participants). DVT incidence was not different between the medication and the combined IPC and medication group (11 studies with 2866 participants). No differences were observed in rates of bleeding (three studies with 244 participants). Further analysis looking at different subgroups of participants did not show any overall difference in incidence of PE and DVT between orthopedic and non‐orthopedic participants.

Quality of the evidence

The findings of this review show moderate quality evidence and agree with current guideline recommendations supporting the use of combined IPC and pharmacological prophylaxis, compared with IPC or pharmacological prophylaxis alone, to reduce the incidence of DVT and PE in hospitalized patients. Moderate quality evidence suggests the addition of pharmacological prophylaxis to IPC, increased the risk of bleeding compared to IPC alone, a side effect not observed for IPC when added to pharmacological prophylaxis (very low quality evidence), as expected for a physical method for preventing blood clots. The quality of the evidence was downgraded from high to moderate or very low for risk of bias and imprecision and indirectness between the studies.

Summary of findings

Background

Description of the condition

Deep vein thrombosis (DVT), i.e. the development of thrombi 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 maximize thromboprophylaxis (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 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

Venous thromboembolism 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 review to assess the breadth and strength of the best available evidence by pooling data from multiple studies to overcome limitations of small and underpowered studies. This review is an update of a review first published in 2008.

Objectives

Methods

Criteria for considering studies for this review

Types of studies

We included randomized controlled trials (RCTs) and controlled clinical trials (CCTs).

Types of participants

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

Types of interventions

We included studies which assessed the combined use of intermittent pneumatic leg compression (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

Venous thromboembolism (symptomatic or asymptomatic) was the main outcome measure, with data on DVT and PE extracted as separate endpoints.

Outcomes were assessed by: ascending venography, I‐125 fibrinogen uptake test and ultrasound scanning for DVT; and pulmonary angiography or scintigraphy, computed tomography (CT), angiography and autopsy for PE.

Secondary outcomes

Bleeding was considered as a safety outcome and included all types reported i.e. 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 was an additional outcome.

Search methods for identification of studies

Electronic searches

For this update the Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (May 2016). In addition the CIS searched the Cochrane Register of Studies (CRS) www.metaxis.com/CRSWeb/Index.asp (CENTRAL (2016, Issue 4)). See Appendix 1 for details of the search strategy used to search the CRS. The Specialised Register is maintained by the CIS and is constructed from weekly electronic searches of MEDLINE, EMBASE, CINAHL, AMED, and through handsearching relevant journals. The full list of the databases, journals and conference proceedings which have been searched, as well as the search strategies used are described in the Specialised Register section of the Cochrane Vascular module in the Cochrane Library (www.cochranelibrary.com).

The following trial databases were searched by the CIS (May 2016) for details of ongoing and unpublished studies using the terms pneumatic compression;

World Health Organization International Clinical Trials Registry (apps.who.int/trialsearch/)

ClinicalTrials.gov (clinicaltrials.gov/)

ISRCTN Register (www.isrctn.com/)

Searching other resources

We searched the reference lists of relevant articles and also similar systematic reviews and meta‐analyses to identify additional trials.

Data collection and analysis

Selection of studies

Two review authors (SK and IN) independently selected studies for inclusion on the basis of use of combined mechanical IPC and pharmacological modalities. Any disagreements were resolved by discussion.

Data extraction and management

SKK and two co‐authors (GG and IN) 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 randomized, 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 author (JC) arbitrated any disagreements.

Assessment of risk of bias in included studies

We assessed the methodological quality of all included studies using Cochrane's 'Risk of bias' tool. . SKK and two co‐authors (GG and IN) independently performed the assessment according to Higgins 2011. The following domains were assessed: 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. Any disagreements were resolved after discussion.

Measures of treatment effect

We performed separate analysis 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 (OR) and risk ratio (RR) with 95% confidence intervals (CIs) for assessment of dichotomous outcomes of all trials and RCTs only, respectively.

Unit of analysis issues

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

Dealing with missing data

In case of missing participants due to drop‐out, 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. I² levels exceeding 50% were considered as substantial heterogeneity to justify the use of random‐effects analysis.

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 by Higgins 2011. 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 RR or ORs and 95% CIs (see Assessment of heterogeneity)..

Subgroup analysis and investigation of heterogeneity

We performed subgroup analysis of the primary outcomes for surgery type (e.g. orthopedic surgery, etc), type of DVT (symptomatic) and type of IPC (foot IPC and other than foot IPC).

Sensitivity analysis

We performed sensitivity analysis of the primary outcomes by excluding studies with a high‐risk for bias, based on the 'Risk of bias' tool, and by excluding CCTs, in order to test the robustness of the evidence. Where significant heterogeneity was present, we performed sensitivity analysis to determine what effect this had on the results.

Summary of findings

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 (GRADEpro GDT 2015) to present the main findings of the review. We included the primary outcomes DVT and PE and incidence of bleeding and 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. The system developed by the Grading of Recommendation, Assessment, Development and Evaluation Working Group (GRADE working group) was used for grading the quality of 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 for the main comparison. 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: patients undergoing surgery or at risk of developing VTE because of other reasons (e.g. trauma) Settings: hospital (surgery, trauma or ICU stay) Intervention: combined IPC plus pharmacological prophylaxis Comparison: IPC alone
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Single modalities	Combined modalities
Incidence of PE^a	8 per 1000	4 per 1000 (1 to 10)	OR 0.49 (0.18 to 1.34)	3017 (12)	⊕⊕⊕⊝  moderate¹
Incidence of DVT^b	41 per 1000	22 per 1000 (14 to 34)	OR 0.52 (0.33 to 0.82)	2934 (11)	⊕⊕⊕⊝  moderate²
Incidence of bleeding^c	7 per 1000	33 per 1000 (16 to 67)	OR 5.04 (2.36 to 10.77)	2155 (7)	⊕⊕⊕⊝ moderate³
Incidence of major bleeding^d	1 per 1000	6 per 1000 (2 to 22)	OR 6.81 (1.99 to 23.28)	2155 (7)	⊕⊕⊕⊝ moderate³
* The basis for the assumed risk was the average risk in the single modalities group (i.e. the number of participants with events divided by total number of participants of the single modalities group included in the meta‐analysis). The corresponding risk (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;IPC: intermittent pneumatic compression; OR: odds ratio; PE: pulmonary embolism; VTE: venous thromboembolism
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Date	Event	Description
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.
3 May 2016	New search has been performed	Search updated. Eleven new studies included, nine new studies excluded and three ongoing studies identified.

Date	Event	Description
14 February 2011	Amended	Link to anticoagulant feedback added.
16 June 2008	Amended	Converted to new review format.

#1	MESH DESCRIPTOR Thrombosis	1211
#2	MESH DESCRIPTOR Thromboembolism	880
#3	MESH DESCRIPTOR Venous Thromboembolism	220
#4	MESH DESCRIPTOR Venous Thrombosis EXPLODE ALL TREES	1978
#5	(thrombus* or thrombopro* or thrombotic* or thrombolic* or thromboemboli* or thrombos* or embol*):TI,AB,KY	16259
#6	MESH DESCRIPTOR Pulmonary Embolism EXPLODE ALL TREES	719
#7	(PE or DVT or VTE):TI,AB,KY	4239
#8	((vein* or ven) near thromb):TI,AB,KY	5893
#9	(blood near3 clot*):TI,AB,KY	2331
#10	(pulmonary near3 clot*):TI,AB,KY	5
#11	(lung near3 clot*):TI,AB,KY	4
#12	MESH DESCRIPTOR Lower Extremity EXPLODE ALL TREES WITH QUALIFIERS BS	1482
#13	#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12	22204
#14	MESH DESCRIPTOR Intermittent Pneumatic Compression Devices EXPLODE ALL TREES	88
#15	MESH DESCRIPTOR Blood Flow Velocity EXPLODE ALL TREES	2246
#16	((pneumati* or sequential) near5 compres*):TI,AB,KY	452
#17	((calf near4 (inflat* or pump* or compres* or squeez*))):TI,AB,KY	95
#18	((foot near4 (inflat* or pump* or compres* or squeez*))):TI,AB,KY	68
#19	((leg near4 (inflat* or pump* or compres* or squeez*))):TI,AB,KY	167
#20	((circulat* near3 assist*)):TI,AB,KY	31
#21	(a‐v impulse):TI,AB,KY	28
#22	(av impulse):TI,AB,KY	7
#23	(flowtron or revitaleg or presssion or plexipulse):TI,AB,KY	4
#24	#14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23	2907
#25	#13 AND #24	569

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of PE	12	3017	Odds Ratio (M‐H, Fixed, 95% CI)	0.49 [0.18, 1.34]
2 Incidence of DVT	11	2934	Odds Ratio (M‐H, Fixed, 95% CI)	0.52 [0.33, 0.82]
3 Incidence of symptomatic DVT	6	2526	Odds Ratio (M‐H, Fixed, 95% CI)	0.49 [0.16, 1.47]
4 Incidence of DVT by foot IPC or other IPC	11	2934	Odds Ratio (M‐H, Fixed, 95% CI)	0.52 [0.33, 0.82]
4.1 foot IPC	1	50	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 other IPC	10	2884	Odds Ratio (M‐H, Fixed, 95% CI)	0.52 [0.33, 0.82]
5 Incidence of bleeding	7	2155	Odds Ratio (M‐H, Fixed, 95% CI)	5.04 [2.36, 10.77]
6 Incidence of major bleeding	7	2155	Odds Ratio (M‐H, Fixed, 95% CI)	6.81 [1.99, 23.28]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of PE	10	3544	Odds Ratio (M‐H, Fixed, 95% CI)	0.39 [0.23, 0.64]
2 Incidence of DVT	11	2866	Odds Ratio (M‐H, Random, 95% CI)	0.42 [0.18, 1.03]
3 Incidence of symptomatic DVT	5	2312	Odds Ratio (M‐H, Fixed, 95% CI)	1.02 [0.29, 3.54]
4 Incidence of DVT by foot IPC or other IPC	11	2866	Odds Ratio (M‐H, Random, 95% CI)	0.42 [0.18, 1.03]
4.1 foot IPC	4	324	Odds Ratio (M‐H, Random, 95% CI)	0.40 [0.05, 3.47]
4.2 other IPC	7	2542	Odds Ratio (M‐H, Random, 95% CI)	0.39 [0.16, 0.96]
5 Incidence of bleeding	3	244	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.30, 2.14]
6 Incidence of major bleeding	3	244	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
1 Incidence of PE	3	605	Odds Ratio (M‐H, Fixed, 95% CI)	0.33 [0.03, 3.19]
2 Incidence of DVT	3	605	Odds Ratio (M‐H, Fixed, 95% CI)	0.83 [0.48, 1.42]
3 Incidence of symptomatic DVT	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Incidence of bleeding	3	616	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [0.27, 5.53]
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
1 Incidence of PE	7	2023	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.09, 2.76]
2 Incidence of DVT	7	2008	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.35, 0.90]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of PE	8	3285	Risk Ratio (M‐H, Fixed, 95% CI)	0.40 [0.24, 0.65]
2 Incidence of DVT	9	2607	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.19, 1.26]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of PE	2	405	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.03, 3.17]
2 Incidence of DVT	2	405	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.50, 1.33]

Methods	Study design: controlled clinical trial  Method of randomisation: study was planned to be randomized and method of planned randomizations was stated as patient order  Concealment of allocation: none stated  Exclusions: none  Losses to follow up: none  Intention‐to‐treat 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: radical retropubic prostatectomy with bilateral pelvic prostatectomy for clinically localized prostate cancer  Exclusion criteria: none stated
Interventions	Intervention group: unfractionated heparin (5000 iu BID, subcutaneously) and sequential compression devices with elastic stockings  Control group: sequential compression devices with elastic stockings
Outcomes	Symptomatic PE, confirmed with ventilation‐perfusion scan
Notes	The study was planned to be randomized but due to administrative errors the randomisation protocol was violated Sequential compression devices were started in the operating room and discontinued when the patients were ambulatory, usually 18 hours postoperatively Heparin was started two hours 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 randomized but due to administrative errors the randomization protocol was violated. Method of planned randomizations 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 patients received heparin
Blinding of participants and personnel (performance bias)   All outcomes	High risk	In most cases the surgeon was aware of which patients received heparin, and the same perhaps applies to the anesthesia 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 patients received heparin
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No patients 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

Trial name or title	The mechanical and medical prevention of lower extremity deep venous thrombosis formation post gynecologic pelvic surgery, a multiple center randomized case control study
Methods	Randomized parallel controlled trial
Participants	Women undergoing gynecologic pelvic surgery
Interventions	GCS: graduated compression stockings; GCS + LMWH: graduated compression stockings + low molecular weight heparin; GCS + IPC: graduated compression stockings + intermittent pneumatic compression; GCS + LMWH + IPC: graduated compression stockings + low molecular weight heparin + intermittent pneumatic compression
Outcomes	DVT on ultrasound of the leg veins (primary); hemoglobin; white blood cell count; hematocrit; platelets; PT; APTT; Fbg; TT; D‐Dimer; AT‐III; t‐PA; PAI; VIII factor; X factor; Protein c; Protein s; CTPA (all secondary)
Starting date	November 2015
Contact information	Cuiqin Sang, 22 South Sanlitun Road, Beijing, China
Notes	Target sample size: GCS: 250; GCS + LMWH: 250; GCS + IPC: 250; GCS + LMWH + IPC: 250

Trial name or title	Efficacy of the association mechanical prophylaxis plus anticoagulant prophylaxis on venous thromboembolism incidence in intensive care unit (ICU) (CIREA2)
Methods	RCT in ICU patients without high risk of bleeding
Participants	621 ICU patients
Interventions	Patients were randomized to use IPC or not
Outcomes	Primary outcome measures: combined criterion evaluated at day 6 ± 2 days after randomization: symptomatic venous thromboembolic 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

Methods	Study design: randomized controlled trial  Method of randomization: unclear  Concealment of allocation: not reported  Exclusions: none  Losses to follow up: none  Intention‐to‐treat analysis: yes
Participants	Country: USA  Number of participants: 48  Age (mean, years): 67  Sex: 47 males, 1 female  Inclusion criteria: major intra‐abdominal surgical procedures  Exclusion criteria: pre‐existing venous disease, history of venous thromboembolism, preoperative or postoperative requirement for systemic anticoagulation (with the exception of the 12 patients undergoing aortic aneurysm repair, who did receive systemic doses of heparin intraoperatively)
Interventions	Intervention group: subcutaneous heparin injections (5000 iu BID) combined with the use of a thigh‐length sequential pneumatic compression device (Kendall Health Care, Manchester, Mass, USA) Control groups:  1. subcutaneous heparin injections (5000 iu BID)  2. use of a thigh‐length sequential pneumatic compression device (Kendall Health Care, Manchester, Mass, USA)
Outcomes	DVT on duplex ultrasound and also clinically evident DVT and PE
Notes	Investigation on the effect of study interventions on fibrinolytic activity, but also reported VTE outcomes DVT prophylaxis was initiated in the operating room after induction of anesthesia and continued until postoperative day 5 (or discharge, if this occurred sooner). If the patient remained hospitalized after postoperative day 5, DVT prophylaxis was left to the discretion of the primary surgeon, and the patient was no longer participating in the research study
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details provided
Allocation concealment (selection bias)	Unclear risk	Not provided
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No placebo anticoagulants or IPC devices were used
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	It is unclear if the personnel who performed the DVT screening were blinded to the treatment regimens
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 was the only VTE outcome event stated in methodology and was reported
Other bias	Low risk	No significant baseline imbalances

Methods	Study design: quasi‐randomized controlled trial  Method of randomization: by the last digit of year of birth  Concealment of allocation: none  Exclusions: not reported  Losses to follow up: not reported  Intention‐to‐treat 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 duplex ultrasonography and clinically evident DVT and PE
Notes	Information on randomization 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‐randomized trial, randomized by the last digit of year of birth
Allocation concealment (selection bias)	High risk	Quasi‐randomized 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 ultrasound tests was not aware of patient 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

Methods	Study design: randomized, double‐blind, placebo‐controlled, superiority trial  Method of randomization: centralized computer‐generated schedule (1:1 randomization in blocks of four and stratified by centre)  Concealment of allocation: yes  Exclusions post randomization: 24  Losses to follow up: none  Intention‐to‐treat analysis: no
Participants	Country: USA  Number of participants: 1309 randomized, 1285 randomized 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 longer than 45 min in patients aged over 40 years; or patients weighing over 50 kg  Exclusion criteria: vascular surgery with evidence of leg ischemia caused by peripheral vascular disease; unable to receive intermittent pneumatic compression 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 venous thromboembolism within the previous 3 months; active bleeding; documented congenital or acquired bleeding disorder; active ulcerative gastrointestinal disease (unless it was the reason for the present surgery); hemorrhagic 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 more than 6 hours after surgical closure; unusual difficulty in achieving epidural or spinal anesthesia; known hypersensitivity to fondaparinux or iodinated contrast medium; current addictive disorders; serum creatinine concentration above 2.0 mg/dL in a well‐hydrated patient; platelet count below 100 000 mm; or patients requiring anticoagulant therapy or other pharmacologic prophylaxis besides intermittent pneumatic compression
Interventions	Intervention group: fondaparinux and intermittent pneumatic compression  Control group: intermittent pneumatic compression
Outcomes	Venous thromboembolism (defined as DVT detected by mandatory screening and/or documented symptomatic DVT or PE, or both) and individual components up to day 10. Symptomatic venous thromboembolism 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 or more) detected during the treatment period Death during the treatment period and up to day 32
Notes	Study medications were packaged in boxes of identical appearance  Of the 1309 randomized patients, 842 (64.3%) had an evaluable venogram performed and were included in the primary efficacy analysis  Major bleeding occurred in 10 patients (1.6%) and 1 patient (0.2%) of the intervention and control groups, respectively (P = 0.006) During the on‐study‐drug period of 5–9 days, all patients were to receive venous thromboembolism prophylaxis with intermittent pneumatic compression 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 hemostasis was achieved. The duration of the on‐study‐drug period was 5–9 days. If the patient was discharged from hospital before completing the on‐study‐drug period, a visiting nurse administered the remaining trial injections
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Centralized computer‐generated schedule randomization (1:1 randomization in blocks of four and stratified by centre)
Allocation concealment (selection bias)	Low risk	Centralized computer‐generated schedule randomization
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 patient allocation
Incomplete outcome data (attrition bias)   All outcomes	High risk	A large number of exclusions in both trial 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 anesthesia, and type and duration of surgery were similar in the two groups among both randomized and treated patients (Tables 1 and 2) and among patients 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‐randomized
Gelfer 2006	Pharmacological prophylaxis was not the same in the two 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 patients 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 two study groups
Mehta 2010	Only aggregated VTE rates and not separate DVT and PE rates were provided and the authors did not reply when individual data were requested
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 two study groups
Stannard 2006	Use of enoxaparin was not concurrent in the two 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 low molecular‐weight heparin and SCDs
Winemiller 1999	Retrospective case‐control study

Trial name or title	The PREVENT Trial: pneumatic compression for PREventing VENous Thromboembolism
Methods	RCT in ICU patients already receiving anticoagulants
Participants	No further information is provided
Interventions	Patients were randomized to use IPC or not
Outcomes	Incidence of proximal leg DVT up to 30 days (primary), PE up to 30 days (secondary), ICU and hospital mortality (secondary)
Starting date	December 2013
Contact information	Dr Yaseen Arabi
Notes	Trial completed, no longer recruiting

PERMALINK

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

Stavros K Kakkos

Joseph A Caprini

George Geroulakos

Andrew N Nicolaides

Gerard Stansby

Daniel J Reddy

Ioannis Ntouvas

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

Summary of findings for the main comparison. 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.

IPC plus pharmacological prophylaxis versus pharmacological prophylaxis alone

2.1. Analysis.

2.2. Analysis.

2.3. Analysis.

2.4. Analysis.

2.5. Analysis.