Intermittent pneumatic compression for treating venous leg ulcers (Review) Nelson EA, Hillman A, Thomas K

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2014, Issue 5 http://www.thecochranelibrary.com

Intermittent pneumatic compression for treating venous leg ulcers (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 IPC plus dressings versus dressings alone, Outcome 1 Number healed in trial. . . . . Analysis 2.1. Comparison 2 IPC plus compression versus compression alone, Outcome 1 Number healed in trial. . Analysis 2.2. Comparison 2 IPC plus compression versus compression alone, Outcome 2 Pain at 6 weeks. . . . . Analysis 3.1. Comparison 3 IPC plus compression versus compression alone - sensitivity analysis, Outcome 1 Number healed in trial. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.2. Comparison 3 IPC plus compression versus compression alone - sensitivity analysis, Outcome 2 Rate of healing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 4.1. Comparison 4 IPC versus compression (bandage or stocking), Outcome 1 Number healed in trial. . . Analysis 5.1. Comparison 5 Fast IPC versus Slow IPC, Outcome 1 Number healed in trial. . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Intermittent pneumatic compression for treating venous leg ulcers (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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[Intervention Review]

Intermittent pneumatic compression for treating venous leg ulcers E Andrea Nelson1 , Alex Hillman2 , Kate Thomas2 1 School

of Healthcare, University of Leeds, Leeds, UK. 2 Cochrane Wounds Group, University of York, York, UK

Contact address: E Andrea Nelson, School of Healthcare, University of Leeds, Baines Wing, Leeds, LS2 9UT, UK. [email protected] Editorial group: Cochrane Wounds Group. Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 5, 2014. Review content assessed as up-to-date: 1 April 2014. Citation: Nelson EA, Hillman A, Thomas K. Intermittent pneumatic compression for treating venous leg ulcers. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD001899. DOI: 10.1002/14651858.CD001899.pub4. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Intermittent pneumatic compression (IPC) is a mechanical method of delivering compression to swollen limbs that can be used to treat venous leg ulcers and limb swelling due to lymphoedema. Objectives To determine whether IPC increases the healing of venous leg ulcers. To determine the effects of IPC on health related quality of life of venous leg ulcer patients. Search methods In April 2014, for this third update, we searched the Cochrane Wounds Group Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. Selection criteria We included randomised controlled trials (RCTs) that compared the effects of IPC with control (sham IPC or no IPC) or made comparisons between IPC treatment regimens, in venous ulcer management. Data collection and analysis Two review authors reviewed titles and abstracts and agreed on full studies to be retrieved. One review author extracted data and assessed studies for risk of bias and this was checked by a second review author. Main results We identified nine randomised controlled trials (including 489 people in total). Only one trial was at low risk of bias overall having reported adequate randomisation, allocation concealment and blinded outcome assessment.

In one trial (80 people) more ulcers healed with IPC than with dressings (62% vs 28%; p=0.002). Five trials compared IPC plus compression with compression alone. Two of these (97 people) found increased ulcer healing with IPC plus compression than with Intermittent pneumatic compression for treating venous leg ulcers (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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compression alone. The remaining three trials (122 people) found no evidence of a benefit for IPC plus compression compared with compression alone. Two trials (86 people) found no difference between IPC (without additional compression) and compression bandages alone. One trial (104 people) compared different ways of delivering IPC and found that rapid IPC healed more ulcers than slow IPC (86% vs 61%). Authors’ conclusions IPC may increase healing compared with no compression. It is unclear whether it can be used instead of compression bandages. There is some limited evidence that IPC may improve healing when added to compression bandages. Rapid IPC was better than slow IPC in one trial. Further trials are required to determine the reliability of current evidence, which patients may benefit from IPC in addition to compression bandages, and the optimum treatment regimen.

PLAIN LANGUAGE SUMMARY Intermittent pneumatic compression for treating venous leg ulcers. Venous leg ulcers (open sores) can be caused by a blockage or breakdown in the veins of the leg. Compression, using bandages or hosiery (stockings), can help heal ulcers. However, they do not always work, and some people are not willing or able to wear them. Intermittent pneumatic compression (IPC) uses an air pump to inflate and deflate an airtight bag wrapped around the leg. This technique is also used to stop blood clots developing during surgery. However, the review of trials found conflicting evidence about whether or not IPC is better than compression bandages and hosiery. Intermittent pneumatic compression (IPC) is better for healing leg ulcers than no compression. . Some studies suggest IPC might be a beneficial addition to bandages for some ulcers, but these studies might be biased. Delivering the IPC therapy in a rapid manner by inflating and deflating the IPC device more quickly resulted in more ulcers being healed than with a slower deflation regime.

BACKGROUND Venous leg ulcers are a common chronic complaint affecting some 3% of the population over the age of 65 years (Callam 1985). They are caused by chronic venous insufficiency, secondary to leg veins being blocked or incompetent. Compression, using roller bandages or hosiery, has been shown to improve ulcer healing rates compared with no compression (Cullum 1997). Bandages or hosiery heal around 70% of venous leg ulcers after 3 to 6 months of treatment (Cullum 1997), but a substantial proportion of patients are not helped by compression bandaging, or are unwilling or unable to wear it. Alternative methods of treating venous leg ulcer patients are required. Intermittent pneumatic compression (IPC) uses an air pump to periodically inflate/ deflate bladders incorporated into sleeves which envelop legs or arms. There are a number of ways of applying intermittent pneumatic compression, using single or multiple chambers / bladders, or by using different types of pumps and compression cycles, for example, variation of inflation and deflation times.

IPC has been used to prevent the development of blood clots during long periods of rest, for example, during surgery. It has also been used to treat limb swelling, for example, lymphoedema, and venous leg ulcers. The purpose of this review is to examine the effectiveness of IPC as a treatment of venous ulcers, and to analyse the evidence for the effectiveness of different IPC regimens.

OBJECTIVES To review the best available evidence for the effects of IPC on venous leg ulcer healing and quality of life. Specific questions addressed by the review are: 1. does IPC increase the healing of venous leg ulcers? 2. what are the relative effects of different IPC regimens? 3. does IPC affect pain or quality of life?

Intermittent pneumatic compression for treating venous leg ulcers (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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METHODS

Criteria for considering studies for this review

Types of studies Randomised controlled trials (RCTs) making the following comparisons: • intermittent pneumatic compression (IPC) compared with a control treatment, namely sham IPC or standard care; • intermittent pneumatic compression (IPC) plus compression compared with compression alone; • one IPC regimen compared with an alternative IPC regimen. Studies performed in the home, in hospital or in any other setting were considered for inclusion in the review.

Types of participants People of any age with venous leg ulcers, irrespective of method of diagnosis of venous insufficiency, and regardless of level of mobility.

Types of interventions IPC applied to the leg. All types of devices were included, for example, below knee or thigh length, single or multiple compartment devices, irrespective of the duration or frequency of treatment.

Types of outcome measures

Primary outcomes

• time to complete healing of ulcers; • proportion of ulcers healing in the trial period; • rate of reduction of ulcer area (expressed either as a percentage or an actual area reduction per unit time).

Secondary outcomes

Search methods for identification of studies

Electronic searches For an outline of the search methods used in second update of this review see Appendix 1. In April 2014, for this third update, we searched the following electronic databases: • The Cochrane Wounds Group Specialised Register (searched 01 April 2014); • The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1); • The Health Technology Assessment Database (HTA) (The Cochrane Library 2014, Issue 1); • Ovid MEDLINE (1946 to March Week 3 2014); • Ovid MEDLINE (In-Process & Other Non-Indexed Citations, March 31, 2014); • Ovid EMBASE (1974 to 2014 March 31); • EBSCO CINAHL (1982 to 01 April 2014) We used the following strategy to search the Cochrane Central Register of Controlled Trials (CENTRAL): #1 MeSH descriptor: [Intermittent Pneumatic Compression Devices] explode all trees #2 (pneumatic near/10 compression*):ti,ab,kw #3 (compression near/10 device*):ti,ab,kw #4 (flowtron or IPC):ti,ab,kw #5 (sequential near/10 compression*):ti,ab,kw #6 #1 or #2 or #3 or #4 or #5 #7 MeSH descriptor: [Leg Ulcer] explode all trees #8 MeSH descriptor: [Varicose Ulcer] explode all trees #9 ((varicose next ulcer*) or (venous next ulcer*) or (leg next ulcer*) or (stasis next ulcer*) or (crural next ulcer*) or “ulcus cruris” or “ulcer cruris”):ti,ab,kw #10 #7 or #8 or #9 #11 #6 and #10 The search strategies for Ovid MEDLINE, Ovid EMBASE and EBSCO CINAHL can be found in Appendix 2, Appendix 3 and Appendix 4 respectively. We combined the Ovid MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision); Ovid format (Lefebvre 2011). We combined the EMBASE search with the Ovid EMBASE filter developed by the UK Cochrane Centre (Lefebvre 2011). There were no restrictions on the basis of date or language of publication and translations of all relevant non-English language papers were obtained using local resources.

• pain and quality of life as measured by validated scales Change in limb volume was not included as an outcome measure as there is only circumstantial evidence that reduction of limb swelling leads to ulcer healing.

Searching other resources We searched the bibliographies of all retrieved and relevant publications identified by these strategies for further studies.

Intermittent pneumatic compression for treating venous leg ulcers (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Data collection and analysis

Selection of studies Two (of four; RM, EAN, AH and KV) review authors independently examined the titles and abstracts of citations generated by the search to identify those likely to meet the inclusion criteria and retrieved these in full. We (RM, EAN, AH or KV) checked full versions of articles to identify those that met the inclusion criteria.

• • • • • • • • •

description of any co-interventions; follow-up period, extent of loss to follow up; results; outcome measures; adverse events; allocation concealment use of intention to treat analysis blinded outcome assessment; and trialists’ conclusions.

Assessment of risk of bias in included studies Data extraction and management We extracted and summarised details of eligible trials using a data extraction sheet. Studies published in duplicate were included only once. One review author undertook data extraction (EAN or AH) and this was checked by a second review author (EAN, RM or KV). One review author undertook the risk of bias assessment (KT or AH) and this was checked by a second review author (EAN). Where available, data were collected on the following (see Characteristics of included studies for detail): • author, title, date of study and publication; • sample size; • participant inclusion and exclusion criteria; • care setting; • baseline variables, for example age, sex, diagnosis, comorbidity, baseline risk, baseline comparability of treatment groups for important variables; • description of interventions; • numbers of participants - both randomised and analysed;

For the update of this review one review author (KT or AH) assessed each included study using the Cochrane Collaboration tool for assessing risk of bias and this was checked by a second review author (EAN) (Higgins 2011). This tool addresses seven specific domains, namely sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting and other bias (e.g. extreme baseline imbalance) (see Appendix 5 for details of criteria on which the judgement is based). We assessed blinding and completeness of outcome data for each outcome separately. We completed a ’Risk of bias’ table for each eligible study and discussed any disagreement to achieve a consensus. We presented an assessment of risk of bias using a ’Risk of bias’ summary figure (Figure 1), which presents all of the judgements in a cross-tabulation of study by entry. This display of internal validity indicates the weight the reader may give the results of each study.

Intermittent pneumatic compression for treating venous leg ulcers (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Figure 1. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.

Intermittent pneumatic compression for treating venous leg ulcers (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Data synthesis Data were entered into and analysed using Cochrane RevMan software. Results are presented with 95% confidence intervals (CI). Estimates for dichotomous outcomes (e.g. number of ulcers healed - yes or no) were reported as risk ratio (RR). Continuous data (e.g. total area healed, or changes in volume of ulcers) were converted to the standardised mean difference (or a weighted mean difference, when plausible) and overall effect size (with 95% CI) calculated. Time to wound healing and time to return to work were analysed as survival (time to event) data, using the appropriate analytical method (as per the Cochrane Reviewers’ Handbook version 5.0.2). Methods of synthesising the studies depend on their quality, design and heterogeneity. Both clinical and statistical heterogeneity were explored. Clinical heterogeneity was explored by examining potentially influential factors such as parameters of IPC used, care setting, co-interventions such as the use of compression therapy. In the absence of clinical and statistical heterogeneity a fixed effect model was applied to pool data. In the presence of statistical heterogeneity (as estimated by the I2 where values greater than 50% indicate the presence of substantial heterogeneity) (Higgins 2003) a random effects model was applied for meta-analysis. Where synthesis is inappropriate we undertook a narrative overview.

RESULTS Description of studies The initial search yielded eight potentially relevant citations to seven studies. Two were controlled clinical trials in venous leg ulcer treatment (Belcaro 1986; Pekenmaki 1987), one mentioned IPC as an additional treatment after a trial of surgical techniques (Sottiurai 1990) resulting in three studies which did not meet the inclusion criteria for the review (see Characteristics of excluded studies). Four studies were included (Coleridge Smith 1989; McCulloch 1994; Rowland 2000; Schuler 1996). For the updates of this review, searches yielded 55 citations. These were considered by two review authors independently and resulted in five additional trials meeting the inclusion criteria (Alvarez 2012; Dolibog 2013; Kumar 2002; Nikolovska 2002; Nikolovska 2005). Nikolovska 2002 was identified from searching the reference list of the included studies. Alvarez 2012 was identified as an ongoing study in the second update, and included in the third update after personal correspondence with the author identified sufficient information to include the study. One study was classified as ’awaiting assessment’ pending full text retrieval (Kussmann 2005), we have been unable to obtain a copy of this paper and therefore have added the citation to the

Characteristics of excluded studies table along with the other 25 citations to 24 studies which did not meet the inclusion criteria for this review. In total, nine RCTs were included in the updated review. The studies were conducted in outpatient department / home environments (7 trials) and outpatient /inpatient (2 trials). The studies are described below in relation to the treatment comparisons.

IPC plus dressings compared with dressings alone (1 trial, 80 participants)

One trial evaluated whether adding IPC to a dressing regimen increased healing rates. (Nikolovska 2002). Nikolovska randomised 80 people (by coin toss) to a hydrocolloid dressings and either standard care (no compression) or IPC: multi-chamber, sequential device with 50 mmHg at ankle and 40 mmHg at thigh, with 3 minute inflation time, 30 seconds at full pressure and 60 second deflation time; 1 hour, five days a week, for up to six months.

IPC plus continuous compression compared with continuous compression alone (5 trials, 219 participants)

Five trials evaluated the effect of adding IPC to a standard regimen of compression bandages or stockings (Alvarez 2012; Coleridge Smith 1989; Kumar 2002; McCulloch 1994; Schuler 1996). Alvarez 2012 compared IPC plus standard compression therapy with compression therapy alone in 52 patients. Compression therapy consisted of a non-adherent primary wound dressing plus a 4layer compression bandage. IPC was performed using a 4-chamber pneumatic leg sleeve and gradient, sequential pump. All pumps were calibrated to a pressure setting of 40-50mmHg, with treatment lasting one hour, twice daily. Inflation and deflation time is not reported. Wounds were measured using a 3 mega pixel digital camera and photo-digital planimetry software. Randomisation was by a computer random number generator. Coleridge Smith 1989, in a trial of 45 people, assessed the addition of IPC to a standard regimen in which ulcers were dressed identically and legs compressed with stockings designed to exert 30 to 40 mmHg graduated compression. A sequential compression device was used to deliver IPC (number of cells is not stated) with higher pressures exerted distally and reducing up the leg. Randomisation was determined by coin tossing. Pre-trial assessment included measurement of ankle brachial pressure index (ABPI), Duplex ultrasound and plethysmographic assessment of venous insufficiency. The 21 participants in the IPC group inserted the ulcerated, stockinged limb into the IPC foot-sleeve daily for up to 4 hours. All patients in the study were advised to elevate their legs while resting, and to avoid standing. Dressings were changed weekly. Ulcer area was measured, by tracing, at the start and at 2

Intermittent pneumatic compression for treating venous leg ulcers (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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weekly intervals during dressing changes, but the baseline comparability of the median ulcer area was poor, the IPC group having larger ulcers than the control group. Kumar 2002 compared IPC plus four-layer bandaging with fourlayer bandaging alone in 47 people. Allocation was by coin toss and data collectors were unblinded. The IPC was a below-knee, single chambered device, with 90 second inflation and 90 second deflation, at 60 mmHg, used for 60 minutes, twice a day, for up to 4 months. This trial recruited 47 people (54 ulcers) but only reported outcomes on the 41 people (48 ulcers) who completed the trial. Kumar 2002 randomised people but included and reported on the number of ulcers healed, some participants had more than one ulcer. This raises concern of a unit of analysis error. McCulloch 1994 compared IPC plus Unna’s Boots with Unna’s Boots alone on 22 patients with venous leg ulcers. IPC was delivered twice a week using a single cell device which compressed the limb uniformly, with care delivered at home. Fifty mmHg of pressure was applied for 90 seconds followed by 30 seconds of relaxation after which legs were dressed in Unna’s Boots. Co-interventions were the same in both groups. “Randomisation” was by case note number. No objective assessment of venous insufficiency was reported. Ulcer area was measured by tracing at dressing changes. Schuler 1996 compared IPC (“HomeRx” sequential gradient compression device) plus elastic stockings with Unna’s Boot therapy alone in 53 participants. The ulcers of people in both groups were dressed with hydrocolloid dressings. All patients were advised to elevate their legs twice daily. The experimental group was supplied with elastic stockings, graded to deliver 30 mmHg at the ankle. These stockings were removed for IPC therapy (“HomeRx”) for 1 hour/am and 2 hours/pm. The “HomeRx” was an IPC device different from those described in other studies and was used to deliver a constant pressure of 10 mmHg to feet, and sequentially 50 mmHg to ankles, 45 mm Hg to calves and 40 mm Hg to thighs. Sequential pressure was delivered at 2.5 second intervals for a total compression time of 10 seconds followed by 60 seconds of no compression. The control group received compression from Unna’s Boots which were changed twice weekly. The method of randomisation was not described. Pre-trial assessment included ABPI measurement and plethysmographic studies of venous insufficiency measuring venous refilling times and venous filling index. Three patients in the control group experienced adverse reactions; cellulitis (1), allergies (2) and were withdrawn from the study. Ulcer area was measured by tracing the outline onto acetate sheets at the start of the trial and at alternate visits. Leg volumes, amount of wound exudate and pain levels were assessed by direct measurement, subjective grading (light, moderate and heavy) and visual analogue scores respectively.

IPC compared with continuous compression (stockings or bandages)(2 trials, 86 participants)

Two trials (Dolibog 2013; Rowland 2000) compared IPC with compression stockings or bandages. Dolibog 2013 compared IPC with two separate compression treatments. 22 people were allocated to 12 chamber IPC, from foot to groin. Pressure was set to 60mmHg at the ankle reducing to 40mmHg at the groin. Ventricular filling time was 60 seconds, with a discharge time of 30 seconds. This was delivered daily with each treatment session lasting for 60 minutes. 23 people were allocated an ulcer stocking system delivering pressure of 30-40mmHg, put on each morning for 10-12 hours and removed at night. 25 people were allocated to two layer short-stretch bandaging. Pressure was standardised at 30-35mmHg or 35-40mmHg. These were applied each morning for 10-12 hours and removed at night. All treatments were given for a period of 15 days. In addition, all participants received 2 months of standard drug therapy and gauze dressings saturated in 0.9% sodium chloride changed daily. For the purposes of our analysis all patients receiving either form of continuous compression were grouped together. Rowland 2000 compared IPC with highly extensible compression bandages worn continuously (Setopress, SSL). Sixteen people with venous leg ulcers were recruited from a wound care outpatient clinic. Randomisation was based on the toss of a coin in this crossover trial (data are only included until the point of cross-over). IPC was delivered using a pump, with pressure set at 50 mmHg, but it was unclear whether a single or multiple cell device was used. Patients were advised to use the IPC device for one hour in the morning and one hour in the evening. People in the control group were treated with high compression, elastomeric bandages. Cointerventions were the same in each group, ulcers were managed according to a local protocol. Ulcer area was measured by tracing at dressing changes.

Comparison of different IPC regimens (1 RCT, 104 participants)

One trial (Nikolovska 2005) of 104 people compared ’rapid’ with ’slow’ IPC. ’Rapid’ IPC has a sleeve inflation time of 0.5 seconds, a 6 second pressure plateau and 12 seconds deflation. The ’slow’ IPC has an inflation time of 60 seconds, a 30 second pressure plateau and 90 seconds deflation time. The IPC device had 7 chambers covering the foot ankle, calf, knee and thigh. Pressure was 45 mmHg at the foot and 30 mmHg at the thigh, for 1 hour daily. Randomisation was by computer generation of a random number sequence, and opening of a sealed opaque, numbered envelope. All patients were treated with a hydrocolloid dressing. Follow up was blinded and was for 6 months. The patients were not treated with compression therapy between IPC sessions. Baseline differences in risk of healing occurred in Nikolovska 2005, where patients in the rapid IPC group tended to have larger ulcers and were of longer duration than those in the slow IPC group (ulcer area mean: 4.47 cm² vs 4.70; ulcer duration mean 4.2 vs 5.4 months). This was the only trial reported using a CONSORT flowchart (Nikolovska

Intermittent pneumatic compression for treating venous leg ulcers (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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2005).

Risk of bias in included studies Only one study was overall at low risk of bias (Nikolovska 2005). This study was at low risk of bias in all domains other than blinding of participants and personnel, which was unclear as it was not reported in the paper). A risk of bias table has been completed for each study. Where possible, a quote has been given as evidence for the judgement. The source of the quote is from the primary reference for each study unless otherwise specified. Allocation

personnel was described, and due to the nature of the treatment it would be clear if IPC was provided. Nikolovska 2005 was judged to be at unclear risk of bias because no blinding was mentioned, but as two IPC regimens were being compared it is unclear whether blinding was attempted. Blinding of outcome assessment: Only Nikolovska 2005 indicated assessment was done by someone unaware of the group (adequate outcome assessor blinding) and was judged to be at low risk of bias. However, one study reported that the outcome assessors were not blinded and hence was judged to be at high risk of bias (Kumar 2002) In six studies it was unclear if the outcome assessors were blinded to the intervention (Alvarez 2012; Coleridge Smith 1989; McCulloch 1994; Nikolovska 2002; Rowland 2000; Schuler 1996). Dolibog 2013 was judged to be at high risk of bias because while the data analysts were blinded to allocation, but the nurse who collected the data was not.

Sequence generation: All nine studies were described as randomised controlled trials, but only seven reported an adequate method of sequence generation and were at low risk of bias for this domain. Four reported the use of a coin toss method to generate the allocation sequence (Coleridge Smith 1989; Kumar 2002; Nikolovska 2002; Rowland 2000 ), and three studies reported the use of computerised methods to generate the allocation sequence (Alvarez 2012; Dolibog 2013; Nikolovska 2005). One study (McCulloch 1994) randomised patients depending on the last digit of their case note number. This was judged to be at high risk of bias as it is a systematic rather than a truly a random allocation. One study (Schuler 1996) did not state the method of random allocation and was judged to be at high risk of bias for this domain.

Allocation concealment: Only two studies reported information which confirmed allocation concealment (Dolibog 2013; Nikolovska 2005). Although these studies did not report the envelopes as being opaque, they did report them to be sequentially numbered and sealed and therefore we judged this to be an adequate method of allocation concealment. Remaining seven studies did not provide any information on allocation concealment and hence were judged to be at unclear risk of bias (Alvarez 2012; Coleridge Smith 1989; Kumar 2002; McCulloch 1994: Nikolovska 2002; Rowland 2000; Schuler 1996). Blinding Blinding of participants and personnel: Eight studies were seen as high risk of bias in the domain of blinding participants and personnel (Alvarez 2012; Coleridge Smith 1989; Dolibog 2013; Kumar 2002; McCulloch 1994; Nikolovska 2002; Rowland 2000; Schuler 1996), These studies were judged to be at high risk of bias because no blinding of participants or

Incomplete outcome data Kumar 2002 was judged to be at low risk of bias for this domain as the number of drop outs was low (n=6, 15%) and balanced across both groups, Rowland 2000 was judged to be at high risk of bias, as whilst an intention to treat analysis was performed, it had a very high withdrawal rate for a small study (5 out of 16 patients withdrew), Alvarez 2012 was seen as low risk of bias as the number of patients allocated to IPC was reported as 25 in the text and 27 in the tables, this appears to be a transcription error. In Coleridge Smith 1989 the information on drop-outs was insufficient to make a judgement. The remaining five studies were judged to be at low risk either because missing data was adequately accounted for or there were no patient withdrawals (Dolibog 2013; McCulloch 1994; Nikolovska 2002; Nikolovska 2005; Schuler 1996).

Selective reporting Reporting bias was judged to be at high risk in Alvarez 2012, as incidence of healing was stated as an outcome measure in the methods but not reported in the results, however this information was supplied in a personal communication with the author. All other studies were judged to be at low risk of reporting bias as all outcome measures stated in the papers were reported. The original protocol was not sought for any of the studies.

Other potential sources of bias Rowland 2000 was the only study identified to have a high risk of bias from another source, it was a crossover RCT with some patients (n=3 ) crossed over after two months, but others crossed over after three months, though criteria for early crossover is not stated, introducing the possibility for physician to introduce bias.

Intermittent pneumatic compression for treating venous leg ulcers (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Effects of interventions The results are presented according to the specific questions addressed by the review as follows:

(1) Does IPC increase the healing of venous leg ulcers?

Three types of comparison sought to address this question. (a) trials comparing IPC with no compression (b) trials comparing IPC plus continuous compression with continuous compression alone (c) trials comparing IPC with continuous compression provided by bandages or hosiery.

(a) IPC compared with no compression More people healed in IPC than in dressings alone (25/40, 62.5% compared with 11/40, 27.5%) this was statistically significant. The risk ratio of healing with IPC was 2.27 (95% CI 1.30 to 3.97)(Nikolovska 2002)(Analysis 1.1). This result is at moderate risk of bias since allocation was not secure (coin toss) and outcome assessment was not blinded.

(b) IPC plus continuous compression compared with continuous compression alone Five trials evaluated the additional effect of IPC over continuous compression (Alvarez 2012; Coleridge Smith 1989; Kumar 2002; McCulloch 1994; Schuler 1996). Alvarez 2012 reported higher healing rate in the IPC group compared with the IPC group, risk ratio 1.49 (95% CI 1.05 to 2.10)(Analysis 2.1). Coleridge Smith 1989 also reported a significantly higher healing rate in the IPC group (10/21) compared with continuous compression where the healing rate was particularly poor (1/24), risk ratio of healing 11.43 (95% CI 1.59 to 81.99)(Analysis 2.1). It is interesting to note that there was imbalance at baseline in the size of ulcers, the median ulcer area for the group allocated to receive IPC plus continuous compression was much larger than the control group. Kumar 2002 reported no significant difference in proportion of ulcers healed : 20/23 (87%) ulcers healed with IPC, while in the bandaging group 23/ 25 (92%). The IPC group, in the trial by Kumar, healed more quickly, in an average (mean) of 53.7 days, compared with the 73.7 days to healing in the bandaging group, but these were not formally compared. The rate of reduction in ulcer area was higher in the IPC group (0.14 cm² per day) than in the bandaging group - 0.05 cm² per day. McCulloch 1994 reported no difference in the proportion of ulcers healed in the IPC and the control group; risk ratio (RR) for healing 1.24 (95% CI 0.89 to 1.75)(Analysis 2.1). Schuler 1996 also reported no difference in the proportion of ulcers healed in the IPC and the control group; risk ratio (RR) for healing 1.19 (95% CI 0.80 to 1.77)(Analysis 2.1).

There was clinical heterogeneity in the type of IPC and substantial statistical heterogeneity (I2 = 77%). Undertaking a sensitivity analysis which excluded Coleridge Smith 1989 still resulted in substantial statistical heterogeneity (I2 = 56%). Undertaking a sensitivity analysis which excluded Coleridge Smith 1989 and Kumar 2002 eliminated statistical heterogeneity (I2 = 0%). Excluding Coleridge Smith 1989 and Kumar 2002 and pooling (fixed effect) the remaining three trials showed a statistically significant difference between the two groups (RR 1.31, 95% CI 1.06 to 1.63)(Analysis 3.1). The duration of IPC evaluated in these trials ranged from 2 to 28 hours per week. Follow-up period was 3 months in one trial (Coleridge Smith 1989), 4 months in the trial by Kumar 2002, 6 months in two trials (McCulloch 1994; Schuler 1996), and 12 months in one trial (Alvarez 2012). McCulloch 1994 and Kumar 2002 used a single cell IPC device, the remaining three studies used a multiple cell device and described the IPC profile as ’sequential’. (c) IPC compared with continuous compression (stockings or bandages) Two trials (Dolibog 2013; Rowland 2000) compared IPC with continuous compression bandages. Dolibog 2013 recruited 70 participants. No statistically significant difference was detected between IPC and two continuous compression regimes. Risk ratio 1.36 (95% CI 0.50 to 3.70). Rowland 2000 recruited 16 participants and reported no statistically significant difference in healing rates between IPC and continuous compression. No patients were healed in this small study before crossover (Analysis 4.1). (2) What are the relative effects of different IPC regimens?

Nikolovska 2005 found that rapid IPC healed more ulcers (45/52) than slow IPC (32/52) , RR 1.41, 95%CI 1.11 to 1.79)(Analysis 5.1). The rapid IPC group not only had more healed ulcers, but healing was achieved in a shorter time: median days to complete ulcer healing was 59 with rapid IPC and 100 days with slow IPC (p=0.001; log rank). (3) Does IPC affect pain or quality of life?

Schuler 1996 reported pain, stating that pain scores, as measured on a visual analogue scale (0-10) were 3.1 (SD 2.3) with Unna’s boot and 2.0 (SD 1.4) with IPC, but that this difference was not statistically significant. The use of different compression systems in this trial, however, confounds the comparison as it is not clear if any difference in pain would be associated with the IPC or the different compression system used. Kumar 2002 stated that comfort was high in both four-layer and IPC groups (8 to 10 on a 0 to 10 scale which was not validated). Alvarez 2012 reported pain, measured using a Visual Analogue Scale (0-10) every week from 0 to 6 weeks. Pain at 6 weeks was 1.5

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(SD 1) for IPC and 2.5 (SD 1.3) for compression alone. Pooling Schuler and Alvarez (I² = 0%; Chi² = 0.03, df = 1 (P = 0.87). The difference in pain scores of 1.03 is statistically significant (-1.03 [95% CI -1.56, -0.49]) but the clinical impact of a 1 point change in pain scale (VAS 0-10) is modest Analysis 2.2.

Study Week

0

1

2

3

4

5

6

IPC Mean and SD

7.8 ± 2.2

5.2 ± 3.1

4.5 ± 2

2.3 ± 2.4

1.9 ± 1.5

2±1

1.5 ± 1

Control Mean and SD

6.9 ± 2.5

7.1 ± 3.3

6 ± 2.5

4.4 ± 3.1

2 ± 1.3

2.2 ± 1.4

2.5 ± 1.3

DISCUSSION With a total of nine trials there are 489 participants who contributed data to this review. The studies are on the whole small, and differ in the type (single-cell compared with sequential: below knee or above knee) and duration of IPC delivered, which does not allow the results to be compared easily. Although one moderately sized trial (Nikolovska 2002) reported that IPC increased healing compared with a dressing alone, this finding is not applicable to the majority of modern settings where compression bandaging is widely used and effective. Were the study to be repeated with people who were intolerant to compression bandaging, then this might provide useful information on a treatment for people who fail to reap the benefit of compression bandages and remain a challenge to practitioners. One small trial reported more ulcers healed with ’fast’ IPC therapy when compared with ’slow’ IPC therapy. Further trials are needed. The small number of trials means that in-depth analysis of heterogeneity cannot be explored. Seven studies described here were undertaken in the community / home care setting and it is unclear whether the place of treatment might have an impact on effectiveness. The other two were undertaken in ’outpatient and inpatient settings at the Clinic of Dermatology, in Skopje in Macedonia. None of the studies offers a rationale for the chosen dose or duration of IPC although each paper describes potential benefits of the specific method of IPC chosen. Four trials assessed the impact of adding IPC to a continuous compression regimen - one added IPC to graduated compression stockings (Coleridge Smith 1989), one to Unna’s Boot (McCulloch 1994), and two studies compared IPCto four-layer compression

(Alvarez 2012; Kumar 2002). At three months, Coleridge Smith 1989 found a statistically significant difference in the percentage of ulcers healed, whilst at four and six months respectively, Kumar 2002 and McCulloch 1994 found no statistically significant difference in the percentage of ulcers healed. At 12 months Alvarez 2012 found a statistically significant difference in the percentage of ulcers healed. It is not clear whether the differences in outcomes between studies is due to the length of follow-up, the type of IPC used, the compression therapy used, or chance. Coleridge Smith 1989 reported very poor outcomes in the control group. Kumar suggested that as compression bandaging alone achieves high healing rates there is little benefit to be gained from adding IPC. The study conducted by Schuler 1996 does not allow the independent effect of IPC to be reliably estimated due to the differences in the methods of compression used in the two groups. Meta-analysis of the three trials (Alvarez 2012; McCulloch 1994; Schuler 1996) assessing the impact of adding IPC to a continuous compression regimen which minimised statistical heterogeneity shows a statistically significant difference in the number of patients healed (RR 1.41 95% CI 1.06 to 1.63). It should be noted that two of these three studies were rated as being at high risk of bias for random sequence generation. Meta-analysis of the two trials reporting pain scores (Alvarez 2012; Schuler 1996) evaluating the impact of adding IPC to a continuous compression regimen on pain shows a small but statistically significant difference in the average pain score, lower pain being associated with IPC (-1.03, 95% CI -1.56, -0.49).

AUTHORS’ CONCLUSIONS Implications for practice IPC improved healing in a poor quality trial, when compared with dressings alone, and this reinforces the finding that continuous

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compression is better than no compression for venous ulcer healing. There is some evidence that the addition of IPC to standard compression may be beneficial. This, however, is based on a small number of small to medium sized studies, which are open to bias. These studies also used different IPC regimens, and there is no evidence as to how long IPC is indicated for, and no evidence as to the optimum IPC regimen. Having said this, there is some evidence that more ulcers healed when a ’fast’ IPC therapy was used, which delivers IPC inflation and deflation of the compression quicker, than with a ’slow’ IPC therapy. There is also some evidence of lower pain scores using IPC over compression.

3. Is IPC an effective alternative to compression bandages / hosiery for some patients who would prefer not to wear compression 24 hours a day ? 4. If IPC is beneficial in any of the above circumstances, what is the optimum IPC regimen? Studies must measure cost data as well as patient outcomes such as quality of life, pain and acceptability of IPC treatment.

ACKNOWLEDGEMENTS Implications for research Larger, well designed RCTs comparing IPC in both hospital and home settings are indicated. Questions that remain to be answered are: 1. Is IPC beneficial in people with venous ulcers who cannot tolerate compression bandages or hosiery ? 2. Is IPC useful as an adjuvant to compression therapy (bandages or hosiery) ?

Trevor Sheldon refereed the original review for clarity and rigour. Suzana Nikolovska translated information on her trial of IPC compared with standard care for inclusion in the review. The Cochrane Wounds Group Editorial base for supporting the review, and the referees for their comments. Sohan Deshpande who entered data associated with the risk of bias assessment into RevMan. Raj Mani and Kath Vowden were authors of the original version of this review and have approved subsequent updates, however they are no longer actively involved in this and future updates of this review, we thank them for their contribution.

REFERENCES

References to studies included in this review Alvarez 2012 {published data only} ∗ Alvarez O, Wendelken M, Markowitz L, Parker R, Comfort C. Effectiveness of Intermittent Pneumatic Compression for the Treatment of Venous Ulcers in Subjects with Secondary (Acquired) Lymphedema. Vein 2012;5(1): 32–34. Alvarez OM, Lullove EJ, Wendelken M, Colon-Cavallito K, Chrzanowski G. Healing Rates and Clinical Benefits of Intermittent Pneumatic Compression (IPC) Therapy in Patients with Chronic Venous Ulcers: Results of a Randomized Controlled Trial in a Single Center and a Retrospective Analysis in 2 Clinical Centers. International Compression Club Meeting. 2013, 8th September. Coleridge Smith 1989 {published data only} Coleridge Smith P, Sarin S, Hasty J, Scurr JH. Improved venous ulcer healing using intermittent pneumatic compression. Phlebologie 1988;41(4):788–9. ∗ Coleridge Smith P, Sarin S, Hasty J, Scurr JH. Sequential gradient pneumatic compression enhances venous ulcer healing: a randomized trial. Surgery 1990;108(5):871–5. Coleridge Smith PD, Sarin SA, Wilson LAA, Scurr JH. Intermittent pneumatic compression improves venous ulcer healing. Phlebologie ’89. Paris: John Libbey Eurotext, 1989:1146–8.

Dolibog 2013 {published and unpublished data} Dolibog P, Franek A, Taradaj J, Polak A, Dolibog, P, Blaszczak E, et al.A randomized, Controlled Clinical Pilot study Comparing three types of Compression therapy to treat Venous Leg ulcers in Patients with superficial and/or segmental deep Venous reflux. Ostotomy/Wound Management 2013;59(8):22–30. Kumar 2002 {published data only} ∗ Kumar S, Samraj K, Nirujogi V, Budnik J, Walker MA. Intermittent pneumatic compression as an adjuvant therapy in venous ulcer disease. Journal of Tissue Viability 2002;12 (2):42–50. Kumar S, Walker A, Gates S, Walker M. Intermittent pneumatic compression as an adjuvant therapy in venous ulcer disease: a randomised trial. Phlebology 2001;16(1): 48–9. McCulloch 1994 {published data only} McCulloch JM, Marler KC, Neal MB, Phifer TJ. Intermittent pneumatic compression improves venous ulcer healing. Advances in Wound Care 1994;7(4):22–6. Nikolovska 2002 {unpublished data only} Nikolovska S, Pavlova LJ, Petrova N, Gocev G. The efficacy of intermittent pneumatic compression in the treatment of venous leg ulcers. Macedonia Medical Review 2002;5:56–9. Nikolovska 2005 {published data only} Nikolovska S, Arsovski A, Damevska K, Gocev G, Pavlova

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L. Evaluation of two different intermittent pneumatic compression cycle settings in the healing of venous ulcers: a randomized trial. Medical Science Monitor 2005;11:337–43. Rowland 2000 {published and unpublished data} Rowland J. Intermittent pneumatic compression versus compression bandages in the treatment of venous leg ulcers. Australian and New Zealand Journal of Surgery 2000;70(2): 110–3. Schuler 1996 {published data only} Schuler JJ, Maibenco T, Megerman J, Ware M, Montalvo J. Treatment of chronic venous ulcers using sequential gradient intermittent pneumatic compression. Phlebology 1996;11(3):111–6.

References to studies excluded from this review Alpagut 2005 {published data only} Alpagut U, Dayioglu E. Importance and advantages of intermittent external pneumatic compression therapy in venous stasis ulceration. Angiology 2005;56(1):19–23. Anderson 2006 {published data only} Anderson I. Venous leg ulcers: methods and devices in compression therapy. Nurse Prescribing 2006;4(6):224–9. Bamigboye 2006 {published data only} Bamigboye AA, Hofmeyr GJ. Interventions for leg edema and varicosities in pregnancy. What evidence?. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2006;129(1):3–8. Belcaro 1986 {published data only} Belcaro G, Coen F. Pneumatic intermittent compression treatment of venous ulcerations caused by chronic venous hypertension. Phlebology ’85. London: Libbey, 1986: 640–2. Bolton 2005 {published data only} Bolton LL. Evidence corner. Comparing a tubular compression device with a short-stretch bandage. A Compendium of Clinical Research and Practice 2005;17(6): A24, A26. Delis 2002 {published data only} Delis KT, Husmann MJ, Nicolaides AN, Wolfe JH, Cheshire NJ. Enhancing foot skin blood flux in peripheral vascular disease using intermittent pneumatic compression: controlled study on claudicants and grafted arteriopaths. World Journal of Surgery 2002;26(7):861–6. Fassiadis 2005 {published data only} Fassiadis N. Patient compliance with venous leg ulcer treatment. Phlebolymphology 2005;48:355–8. Fogh 2006 {published data only} Fogh K, Hansson C. News in the treatment of venous leg ulcers. Forum for Nordic Dermato-Venerology 2006;11(1): 14–8. Gale 2004 {published data only} Gale SS, Shuman S, Beebe HG, Pigott JP, Comerota AJ. Percutaneous venous valve bioprosthesis: Initial observations. Vascular and Endovascular Surgery 2004;38 (3):221–4.

Grieveson 2003 {published data only} Grieveson S. Intermittent pneumatic compression pump settings for the optimum reduction of oedema. Journal of Tissue Viability 2003;13(3):98–104. Junger 2004 {published data only} Junger M, Partsch H, Ramelet A, Zuccarelli F. Efficacy of a ready-made tubular compression device versus short-stretch compression bandages in the treatment of venous leg ulcers. Wounds - A Compendium of Clinical Research and Practice 2004;16(10):313–20. Junger M, Partsch H, Ramelet AA, Zuccarelli F. Efficacy of a new compression device versus bandages in the treatment of venous leg ulcers. 2nd World Union of Wound Healing Societies’ Meeting, Paris. 2004:11. Kakkos 2005 {published data only} Kakkos SK, Griffin M, Geroulakos G, Nicolaides AN. The efficacy of a new portable sequential compression device (SCD Express) in preventing venous stasis. Journal of Vascular Surgery 2005;42(2):296–303. Kalodiki 2007 {published data only} Kalodiki E. Use of intermittent pneumatic compression in the treatment of venous ulcers. Future Cardiology 2007;3 (2):185–91. ∗ Kalodiki E, Ellis M, Kakkos SK, Williams A, Davies AH, Geroulakos G. Immediate hemodynamic effect of the additional use of the SCD EXPRESS compression system in patients with venous ulcers treated with the fourlayer compression bandaging system. European Journal of Vascular and Endovascular Surgery 2007;33(4):483–7. Kolbach 2006 {published data only} Kolbach DN, Sandbrink MWC, Neumann HAM, Prins MH. Compression therapy for treating stage I and II (Widmer) post-thrombotic syndrome. Cochrane Database of Systematic Reviews 2003, Issue 4. [DOI: 10.1002/ 14651858.CD004177] Kussmann 2005 {published data only} Kussmann KS. Intermittent pneumatic compression therapy - ’Pro’. Lymphologie in Forschung und Praxis 2005;9 (2):107–8. Murakami 2003 {published data only} Murakami M, McDill TL, Cindrick-Pounds L, Loran DB, Woodside KJ, Mileski WJ, et al.Deep venous thrombosis prophylaxis in trauma: improved compliance with a novel miniaturized pneumatic compression device. Journal of Vascular Surgery 2003;38(5):923–7. Omar 2004 {published data only} Omar AA, Mavor AID, Jones AM, Homer-Vanniasinkam S. Treatment of venous leg ulcers with Dermagraft. European Journal of Vascular and Endovascular Surgery 2004;27(6): 666–72. Partsch 2006 {published data only} Partsch H. Compression therapy of venous ulcers: haemodynamic effects depend on interface pressure and stiffness. EWMA Journal 2006;6(2):16–20.

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Pekenmaki 1987 {published data only} Pekanmaki K, Kolari PJ, Kiistala U. Intermittent pneumatic compression treatment for post-thrombotic leg ulcers. Clinical and Experimental Dermatology 1987;12:350–3. Rajendran 2007 {published data only} Rajendran S, Rigby AJ, Anand SC. Venous leg ulcer treatment and practice--Part 3 The use of compression therapy systems. Journal of Wound Care 2007;16(3):107–9. Robson 2006 {published data only} Robson MC, Cooper DM, Aslam R, Gould LJ, Harding KG, Margolis DJ, et al.Guidelines for the treatment of venous ulcers. Wound Repair and Regeneration 2006;14(6): 649–62. Rudicel 2001 {published data only} Rudicel S. Intermittent pneumatic compression promoted healing in foot infections. Journal of Bone and Joint Surgery. American Volume 2001;83-A(5):787. Scheur 1999 {published data only} Scheur van de MR, Kessels F, Sommer A, et al.Intermittent pneumatic compression as alternative for compressive bandages in the out patient management of venous ulceration and venous oedema. A pilot study in costminimisation. Scripta Phlebologica 1999;7:3–6. Sottiurai 1990 {published data only} Sottiurai VS. Comparison of surgical modalities in the treatment of recurrent venous ulcer. International Angiology 1990;9(4):231–5. Stephen 2006 {published data only} Stephen-Haynes J, Lindsay E, Muldoon J. Easing compression hosiery application: ActiGlide. British Journal of Community Nursing 2006;11(9):S21–2. Trzeciak 2004 {published data only} Trzeciak S, Dellinger RP. Other supportive therapies in sepsis: an evidence-based review. Critical Care Medicine 2004;32(11):S571–7. Wang 2007 {published data only} Wang SM, Yao C. Diagnosis and treatment of chronic venous ulcer: Research status and new strategies. Acta Academiae Medicinae Sinicae 2007;29(1):5–8.

Wienert 2005 {published data only} Wienert V, Partsch H, Gallenkemper G, Gerlach H, Junger M, Marschall M, et al.Guideline: Intermittent pneumatic compression. Phlebologie 2005;34(3):176–80.

Additional references Callam 1985 Callam MJ, Ruckley CV, Harper DR, Dale JJ. Chronic leg ulceration: the extent of the problem and the provision of care. BMJ 1985;290:1855–6. Cullum 1997 Cullum N, Fletcher A, Semlyen A, Sheldon TA. Compression therapy for venous leg ulcers. Quality in Health Care 1997;6:226–31. Higgins 2003 Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. BMJ 2003;327 (7414):557–60. Higgins 2011 Higgins JPT, Altman DG, on behalf of the Cochrane Statistical Methods Group and the Cochrane Bias Methods Group (Editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Lefebvre 2011 Lefebvre C, Manheimer E, Glanville J, on behalf of the Cochrane Information Retrieval Methods Group. Chapter 6: Searching for studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.orgg. ∗ Indicates the major publication for the study

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CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Alvarez 2012 Methods

RCT involving comparing IPC plus standard compression therapy with standard compression therapy alone Outcome measures determined by measurements taken by a 3 mega pixel digital camera and photo-digital planimetry software taken at baseline weekly follow up for 12 months Intention to treat analysis was not required as none of the participants withdrew

Participants

52 patients with venous ulcers participated (25 IPC plus standard compression therapy and 27 standard compression therapy alone) Clear inclusion/exclusion criteria. Groups comparable at baseline.

Interventions

The ulcers of the control subjects were dressed and bandaged using the Profore™ 4layer bandage system (4 LB,Figure 1, Smith and Nephew, Largo FL). Dressings for most patients changed twice weekly The IPC group received the same dressings as the control group, and in addition compression therapy was provided by a 4-chamber intermittent gradient, sequential, pneumatic compression device (Sequential Circulator Model 2004, BioCompression Inc. Moonachie, NJ). This was provided twice daily for one hour at a pressure of 40-50 mmHg while the subject was in a reclining or decubitus position

Outcomes

22/25 (88%) IPC patients healed at 12 months compared with 16/27 (59.2%) control. (RR 1.49 95% CI 1.05 to 2.10) Mean rate of healing 1.7mm2 /day IPC compared with 0.8mm2 /day control. (mean difference 0.9mm2 /day 95% CI -4.41 to 6.21)

Notes

No patient withdrawals from study. Experimental and control groups comparable at baseline.

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

Quote: “Those who qualified were assigned to either the IPC or control treatment groups according to a computer generated randomization schedule” (P33 “study design and study population”) Comment: Adequate random method of assignment described.

Allocation concealment (selection bias)

Comment: Allocation concealment not described

Unclear risk

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Alvarez 2012

(Continued)

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

Comment: No blinding described. Due to the nature of the intervention it would be clear to patients and clinicians whether IPC was applied

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

Comment: No blinding described.

Incomplete outcome data (attrition bias) All outcomes

Low risk

Quote: “A total of 52 subjects were treated with 27 randomized to compression bandage therapy alone (control) and 25 to IPC therapy” (P33 “Study design and study population” P34 Table 1.) Comment: No participant drop out is reported, and outcome data is given for 52 subjects. However, in table 1 IPC group is stated to be 27 people and control group 25 people, this appears to be a transcription error

Selective reporting (reporting bias)

High risk

Comment: Inciudence of healing stated as outcome measure but not reported

Other bias

Low risk

Comment: No other risk of bias described.

Coleridge Smith 1989 Methods

RCT comparing IPC with graduated compression stockings 30-40 mmHg in a hospital/ home setting. Outcome measure determined from ulcer contour traces at entry, 2,4,8,12 weeks and then at 4 weekly intervals to healing or 3 months. Allocation concealment: NO (coin toss) Ulcer area much larger at baseline in the IPC group ITT analysis: Probably as no mention of withdrawals Blinded outcome assessment: Not clear

Participants

45 patients with venous leg ulcers Median ulcer area at baseline: IPC group 49.8 cm² (inter-quartile range 12.7-135) Control group 17.3 cm² (inter-quartile range 13.0-31.0) Poor baseline comparability

Interventions

Sequential IPC applied for up to 4 hours daily in IPC group. IPC group received the same dressings and stocking regimen as control group

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Coleridge Smith 1989

(Continued)

Outcomes

10/21 (48%) patients in IPC group healed compared with 1/24 (4%) in control. (RR 11.43, 95% CI 1.59 to 82) Median rate of reduction in area was 19.8% per week in IPC group compared with 2. 1% per week in control group

Notes

Ulcers not stratified. No quality of life assessments provided. Ulcer area much larger at baseline in the IPC group.

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

Quote: “Patients were randomly allocated… according to the toss of a coin” (p872 “patients and methods” paragraph 2)

Allocation concealment (selection bias)

Comment: Allocation concealment not described.

Unclear risk

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

Comment: No blinding described. Due to the nature of the intervention it would be clear to patients and clinicians whether IPC was applied

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

Comment: No blinding described.

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

Comment: Patient numbers first stated in results section, though no withdrawal reported

Selective reporting (reporting bias)

Low risk

Comment: All outcomes stated in method were reported in the results. Protocol not sought

Other bias

Unclear risk

Comment: No other risk of bias identified

Dolibog 2013 Methods

RCT comparing IPC with two other interventions: an ulcer stocking system and a two layer short-stretch bandage system Outcomes measured by digital planimetry at baseline before the start of the intervention, and after 15 days at the end of the intervention

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Dolibog 2013

(Continued)

Participants

70 patients with venous leg ulcers. Clear inclusion/exclusion criteria Patient characteristics did not vary significantly between groups

Interventions

All participants received 2 months of standard drug therapy and gauze dressings saturated in 0.9% sodium chloride changed daily Those allocated to IPC were given 60 minutes of IPC daily for 15 days. Cuff length 109cm extending from foot to thigh. Pressure 60mmHg at ankle decreasing to 40mmHg at groin. Ventricular filling time was 60 seconds and discharge time 30 seconds. Those allocated to an ulcer stocking system had stockings put on the leg each morning in outpatient clinic, worn for 10-12 hours and removed at night, for 15 days. Stockings provided 30mmHg to 40mmHg at the ankle. Those allocated to a two-layer short-stretch bandaging wore the bandaging during the day (for 10-12 hours) and removed them at night, daily for 15 days. Pressure values measured at 30-35mmHg or 35-40mmHg.

Outcomes

IPC group: 5/22 healed. Continuous pressure groups: 8/48 healed. RR 1.36 (95% CI 0.5-3.7)

Notes

No patient withdrawals from study. Experimental and control groups comparable at baseline.

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

Quote: “Computer generated random numbers “ (p24 “Design and criteria” final paragraph)Comment: Random allocation method described and adequate

Allocation concealment (selection bias)

Quote: “Computer generated random numbers were sealed in a predetermined amount of sequentially numbered envelopes” (p24 “Design and criteria” final paragraph)

Low risk

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

Comment: No blinding described. Due to the nature of the intervention it would be clear to patients and clinicians whether IPC was applied

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

Quote: “A nurse from the hospital collected all data and coded it…the blinded results were transferred… by a technician… The research coordinators had no contact with patients and could not identify them” (p25 “Data collection”) “Nurse... not blinded”

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Dolibog 2013

(Continued)

(personal correspondence with Dolibog) Comment: Those who conducted data analysis were blinded, but the assessors recording outcome measures were not, so introduction of bias here remains possible Incomplete outcome data (attrition bias) All outcomes

Low risk

Comment: No participant withdrawal reported.

Selective reporting (reporting bias)

Low risk

Comment: All outcome measures stated in method reported in results. Original protocol not sought

Other bias

Low risk

Comment: No other risk of bias identified.

Kumar 2002 Methods

RCT comparing four-layer bandaging with bandaging plus IPC. Allocation by coin toss. ITT analysis: No

Participants

47 people with 54 venous ulcers (22 people (26 ulcers) in IPC group and 25 people (28 ulcers) in bandages group). Clear information on inclusion / exclusion criteria. No data on baseline comparability.

Interventions

Non-sequential below knee IPC. 90 s inflation, 90 s deflation; 60 minutes twice a day for 4 months. All received four-layer bandaging weekly.

Outcomes

Group 1: 20/23 ulcers (in 19 people) healed in IPC group (87%): Group 2: 23/25 ulcers (in 22 people) healed (92%)

Notes

Six people (6 ulcers) withdrew out of 47: 3 from IPC: pain, electricity cost, family doctor request 3 from control (no information)

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

Quote: “Randomization by the toss of a coin” (p44 “Methods” first paragraph) Comment: Random allocation method described and adequate.

Allocation concealment (selection bias)

Comment: Allocation concealment not described.

Unclear risk

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Kumar 2002

(Continued)

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

Comment: No blinding described. Due to the nature of the intervention it would be clear to patients and clinicians whether IPC was applied

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

Quote: “without blinding of data collectors” (p44 “Methods” first paragraph) Comment: We have assumed that the reference to data collectors means those assessing outcome measures

Incomplete outcome data (attrition bias) All outcomes

Low risk

Quote: “Three patients were withdrawn from the active group… The control group…three were withdrawn” Comment: 15% attrition, equal across both groups.

Selective reporting (reporting bias)

Low risk

Comment: All outcome measures specified in the methods were reported in the results. Protocol not sought

Other bias

Low risk

Comment: No risk of bias identified.

McCulloch 1994 Methods

RCT involving 22 patients(12 test and 10 controls). Both groups treated with dressings and Unna’s Boots. IPC group received single-cell IPC. Study setting home. Patients followed by 2 investigators 2/daily for 6 months or wound healing. Ulcer contours traced. Allocation concealment - unclear. ITT analysis: Yes

Participants

22 patients with venous leg ulcers. Range of ulcer areas at baseline (no mean or median values provided): IPC, range = 0.37 to 45.03 cm² Control, range 0.36 to 59.35 cm² . Mean age of person at baseline: IPC group, mean = 60 years Control group, mean = 80 years Poor data on baseline comparability.

Interventions

Single cell IPC for 1 hour twice weekly throughout study

Outcomes

12/12 (100%) ulcers in IPC group healed compared with 8/10 (80%) in control group. (RR 1.25, 95% CI 0.92 to 1.70). Mean healing rate was 0.15 cm² per day in IPC group compared with 0.08 cm² in controls (p=0.05, t-test)

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McCulloch 1994

(Continued)

Notes

2/12 IPC patients were semi-mobile and 1 patient with bilateral ulcers was included in both groups. Patients in the control group were older than those in the IPC group. Not clear whether ulcer area at the start of trial were comparable in two groups

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection High risk bias)

Quote: “Randomly assigned to a control or experimental group depending on the last digit (even/odd) of their medical record number” (p23 “Methods” first paragraph) “One patient had an ulcer on each extremity and therefore served as a control and experimental subject” (p24 “Results” first paragraph) Comment: This is a systematic, not random method of assignment. The method was broken to allow one patient into both groups

Allocation concealment (selection bias)

Comment: Allocation concealment not reported

Unclear risk

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

Comment: No blinding described. Due to the nature of the intervention it would be clear to patients and clinicians whether IPC was applied

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

Comment: No blinding described.

Incomplete outcome data (attrition bias) All outcomes

Low risk

Quote: “complete healing of all ulcers occurred in 8 out of 10 control subjects and all 12 of the experimental subjects” (p24 “Results” second paragraph) Comment: Does not explicitly state that all participants recruited completed the trial, however no withdrawal of participants is stated, and results are reported for 22 participants

Selective reporting (reporting bias)

Low risk

Comment: All outcomes stated in method were reported in results. Original protocol not sought

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McCulloch 1994

(Continued)

Other bias

Low risk

Comment: No other risk of bias identified

Nikolovska 2002 Methods

RCT involving 80 people. 40 in each group. Generation of allocation sequence was by coin toss - allocation concealment was not described. ITT analysis: yes. Blinded outcome assessment: not stated.

Participants

80 people with venous ulcers in Skopje, Macedonia. In-patients and out-patients. ABPI at least 0.8. Clear inclusion / exclusion criteria. Patients comparable at baseline.

Interventions

Thigh length multi-chambered, sequential IPC (50 mmHg at ankle, and 40 mmHg at thigh). Inflation 3 seconds, high pressure for 30 seconds, deflation 60 seconds. 60 minutes a day for 5 days a week. 6 months of treatment. Other treatments included dressings but NO compression therapy

Outcomes

Number of ulcers healed at 6 months: IPC 25/40 (62.5%) Control 11/40 (27.5%).

Notes

trial author provided translation of data 7/80 withdrew.

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

Quote: “Method of generation of randomization sequence was coin toss” Comment: Random allocation procedure described and adequate.

Allocation concealment (selection bias)

Quote: “Allocation concealment was not described” Comment: Allocation concealment was not described.

Unclear risk

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

Comment: No blinding described. Due to the nature of the intervention it would be clear to patients and clinicians whether IPC was applied

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

Comment: No blinding described

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Nikolovska 2002

(Continued)

Incomplete outcome data (attrition bias) All outcomes

Low risk

Quote: “Seven patients were withdrawn from the study but were included in the analysis as treatment failures” Comment: Intention to treat analysis performed as stated.

Selective reporting (reporting bias)

Low risk

Comment: Outcome measures specified in the methods reported in the results. Protocol not sought

Other bias

Unclear risk

Comment: No other source of bias identified.

Nikolovska 2005 Methods

RCT of 104 people with venous ulcers in Skopje, Macedonia. Generation of allocation sequence by computers and allocation was by sealed, sequentially numbered, envelopes. ITT analysis: yes Blinded outcome assessment: yes

Participants

104 people with venous ulcers (ABPI at least 0.8) plus evidence of chronic venous pathology. Clear inclusion and exclusion criteria. Groups comparable at baseline.

Interventions

Fast IPC inflated for 0.5 seconds, stay compressed for 6 seconds and deflate over 12 seconds. Slow IPC inflated over 60 seconds, stayed compressed for 30 s and deflated over 90 seconds. All received dressings and no report of compression bandages

Outcomes

Fast IPC healed 45/52 (86%) and slow IPC healed 32/52 (61%) in 6 months. Healing rate per day:(mean) Fast IPC: 0.09 (0.09 SD) Slow IPC: 0.04 (0.03 SD). Faster healing in Fast IPC - median 59 days versus 100 days in slow IPC

Notes

13/104 withdrew.

Risk of bias Bias

Authors’ judgement

Random sequence generation (selection Low risk bias)

Intermittent pneumatic compression for treating venous leg ulcers (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Support for judgement Quote: “For each participant a computerized random number was generated” (CR338 “Materials and Methods” paragraph 5) Comment: Random allocation method de22

Nikolovska 2005

(Continued)

scribed and adequate. Allocation concealment (selection bias)

Low risk

Quote: “The particular regimen of compression was allocated by opening the correspondingly numbered sealed opaque envelope” (CR338 “Materials and Methods” paragraph 5) Comment: Adequate allocation concealment described.

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

Comment: No blinding described.

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

Quote: “The evaluation was made by an observer blinded to the compression regimen used” (CR339 “Material and methods” paragraph 10) Comment: Outcome assessment adequately blinded.

Incomplete outcome data (attrition bias) All outcomes

Low risk

Quote: “In this intention-to-treat analysis all dropouts were retained in the statistical analysis as treatment failure” (CR339 “Material and methods” paragraph 13) Comment: Lost to follow up rapid IPC 3/52 (5.7%) slow IPC 10/52 (19.2%) (CR339 figure 1). Intention to treat analysis performed as described

Selective reporting (reporting bias)

Low risk

Comment: All outcome measures specified in the method were reported in the results. Protocol not sought

Other bias

Low risk

Comment: No other risk of bias identified.

Rowland 2000 Methods

RCT (crossover after 2 or three months) of 16 patients. Both groups were treated with dressings according to local protocol. Blinded outcome assessment: not stated

Participants

16 people attending the Liverpool Wound Healing Clinic. People with diabetes, dermatitis, cardiac failure, deep venous thrombosis, a severe leg deformity or an ABPI < 0. 8 were excluded. No data on baseline comparability.

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Rowland 2000

(Continued)

Interventions

IPC group had treatment for 2 to 3 months. Pressure of 50 mmHg was applied for 1 hour in both the morning and evening. Control group wore a Setopress bandage.

Outcomes

Treatment group: no-one healed before cross-over Control group: no-one healed before cross-over

Notes

Author reported that patients preferred the IPC over the bandage but no data were presented

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

Quote: “Randomization occurred according to the toss of a coin” Comment: Random method of generation reported and adequate.

Allocation concealment (selection bias)

Comment: Allocation concealment not described.

Unclear risk

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

Comment: No blinding described. Due to the nature of the intervention it would be clear to patients and clinicians whether IPC was applied

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

Comment: No blinding described.

Incomplete outcome data (attrition bias) All outcomes

High risk

Quote: “After deletion of five subjects because of missing data, 11 valid cases were left for study… Three patients were from the pump group and two were from the bandages group… intention-to-treat analysis… performed”. (p111 “Results” paragraph 1) Comment: Does not state how the missing data were treated in the intention to treat analysis. Reasons for missing data not given. High rate of attrition in small study (31%)

Selective reporting (reporting bias)

Low risk

Comment: All outcomes stated in method reported in results, protocol not sought

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Rowland 2000

(Continued)

Other bias

High risk

Quote: “Depending on the rate of healing as determined by the treating physician at the 2-month visit, and were then crossed over to receive the alternative therapy” Comment: Crossover Randomized Control Trial design. Criteria for early crossover not stated, introducing the possibility for physician to introduce bias

Schuler 1996 Methods

IPC compared with Unna’s Boots (UB) in 53 patients. IPC group wore elasticated stockings which were removed for IPC delivered through a ”HomeRx“ sequential gradient compression device. Ulcer dressings were uniform for both groups. Ulcer contours traced. Follow-up 180 days

Participants

53 patients with venous ulcers. Mean (SD) area of ulcer: IPC group 9.7 (7.7) cm² Unna’s Boot 10.1 (8.9) cm² Limited data on baseline comparability but report states the two groups were demographically identical

Interventions

IPC bilaterally for 1 hour each morning and 2 hours each evening for study period. Unna’s Boot reapplied at least weekly.

Outcomes

20/28 (71%) patients healed completely in IPC group compared with 15/25 (60%) in UB group. 76% ulcers healed in IPC group compared with 65% in UB group (not significant) when analysed by the life table method, taking into account the patients who dropped out of the study

Notes

Levels of pain and exudate decreased in test group. Adverse reaction to Unna’s Boots reported. Ulcer area at baseline appears similar in the two groups.

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection High risk bias)

Quote: “Patients… were randomized” (p112 “Methods” paragraph 1) Comment: Method of randomization not stated.

Allocation concealment (selection bias)

Comment: Allocation concealment not stated.

Unclear risk

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Schuler 1996

(Continued)

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

Comment: No blinding described. Due to the nature of the intervention it would be clear to patients and clinicians whether IPC was applied

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

Comment: No blinding described.

Incomplete outcome data (attrition bias) All outcomes

Low risk

Quote: “patients who experienced adverse reactions were considered as having completed the study with their ulcer still unhealed” and “non-compliance… were simply censored” (p113 “Methods” final paragraph) Comment: 15% Attrition. Limited ITT analysis performed, with assumptions of missing data stated

Selective reporting (reporting bias)

Low risk

Comment: All outcome measures specified in paper reported, though protocol not sought

Other bias

High risk

Quote: “When two or more ulcers were present, the one ‘most intermediate’ in size was chosen to be studied.”(p112 “Methods” paragraph 1) Comment: Method for determining “most intermediate” ulcer not described

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Alpagut 2005

not randomised

Anderson 2006

not a systematic review / trial

Bamigboye 2006

not a venous ulcer population

Belcaro 1986

CCT

Bolton 2005

not a systematic review / trial

Delis 2002

not a venous ulcer population

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(Continued)

Fassiadis 2005

not a systematic review / trial

Fogh 2006

not a systematic review / trial

Gale 2004

not a venous ulcer population

Grieveson 2003

not a venous ulcer population

Junger 2004

trial of compression bandage system

Kakkos 2005

not a venous ulcer population

Kalodiki 2007

not a venous ulcer population

Kolbach 2006

not a venous ulcer population

Kussmann 2005

unable to obtain a full text copy of the study report for assessment

Murakami 2003

not a venous ulcer population

Omar 2004

treatment not IPC

Partsch 2006

treatment not IPC

Pekenmaki 1987

open uncontrolled study

Rajendran 2007

not a systematic review / trial

Robson 2006

not a systematic review / trial

Rudicel 2001

not a venous ulcer population

Scheur 1999

not randomised

Sottiurai 1990

evaluates use of IPC after surgery

Stephen 2006

not trial of IPC

Trzeciak 2004

not a venous ulcer population

Wang 2007

not a systematic review / trial

Wienert 2005

not a systematic review / trial

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DATA AND ANALYSES

Comparison 1. IPC plus dressings versus dressings alone

Outcome or subgroup title 1 Number healed in trial

No. of studies

No. of participants

1

Statistical method Risk Ratio (M-H, Fixed, 95% CI)

Effect size Totals not selected

Comparison 2. IPC plus compression versus compression alone

Outcome or subgroup title 1 Number healed in trial 2 Pain at 6 weeks

No. of studies

No. of participants

5 2

105

Statistical method Risk Ratio (M-H, Random, 95% CI) Mean Difference (IV, Fixed, 95% CI)

Effect size Totals not selected -1.03 [-1.56, -0.49]

Comparison 3. IPC plus compression versus compression alone - sensitivity analysis

Outcome or subgroup title 1 Number healed in trial 2 Rate of healing

No. of studies

No. of participants

3 1

127 52

Statistical method Risk Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)

Effect size 1.31 [1.06, 1.63] 0.90 [-4.41, 6.21]

Comparison 4. IPC versus compression (bandage or stocking)

Outcome or subgroup title 1 Number healed in trial

No. of studies 2

No. of participants

Statistical method Risk Ratio (M-H, Random, 95% CI)

Intermittent pneumatic compression for treating venous leg ulcers (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Effect size Totals not selected

28

Comparison 5. Fast IPC versus Slow IPC

Outcome or subgroup title 1 Number healed in trial

No. of studies

No. of participants

1

104

Statistical method

Effect size

Risk Ratio (M-H, Fixed, 95% CI)

1.41 [1.11, 1.79]

Analysis 1.1. Comparison 1 IPC plus dressings versus dressings alone, Outcome 1 Number healed in trial. Review:

Intermittent pneumatic compression for treating venous leg ulcers

Comparison: 1 IPC plus dressings versus dressings alone Outcome: 1 Number healed in trial

Study or subgroup

Nikolovska 2002

IPC plus dressing

Dressing alone

n/N

n/N

25/40

11/40

Risk Ratio

Risk Ratio

M-H,Fixed,95% CI

M-H,Fixed,95% CI 2.27 [ 1.30, 3.97 ]

0.1 0.2

0.5

Favours dressing

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1

2

5

10

Favours IPC

29

Analysis 2.1. Comparison 2 IPC plus compression versus compression alone, Outcome 1 Number healed in trial. Review:

Intermittent pneumatic compression for treating venous leg ulcers

Comparison: 2 IPC plus compression versus compression alone Outcome: 1 Number healed in trial

Study or subgroup

IPC + compression

Compression

Risk Ratio MH,Random,95% CI

Risk Ratio MH,Random,95% CI

n/N

n/N

Alvarez 2012

22/25

16/27

1.49 [ 1.05, 2.10 ]

Coleridge Smith 1989

10/21

1/24

11.43 [ 1.59, 81.99 ]

Kumar 2002

20/23

23/25

0.95 [ 0.78, 1.15 ]

McCulloch 1994

12/12

8/10

1.24 [ 0.89, 1.75 ]

Schuler 1996

20/28

15/25

1.19 [ 0.80, 1.77 ]

0.01

0.1

1

Favours compression

10

100

Favours IPC + comp

Analysis 2.2. Comparison 2 IPC plus compression versus compression alone, Outcome 2 Pain at 6 weeks. Review:

Intermittent pneumatic compression for treating venous leg ulcers

Comparison: 2 IPC plus compression versus compression alone Outcome: 2 Pain at 6 weeks

Study or subgroup

IPC + compression

Mean Difference

Compression

Weight

IV,Fixed,95% CI

Mean Difference

N

Mean(SD)

N

Mean(SD)

IV,Fixed,95% CI

Alvarez 2012

25

1.5 (1)

27

2.5 (1.3)

73.3 %

-1.00 [ -1.63, -0.37 ]

Schuler 1996

28

2 (1.4)

25

3.1 (2.3)

26.7 %

-1.10 [ -2.14, -0.06 ]

Total (95% CI)

53

100.0 % -1.03 [ -1.56, -0.49 ]

52

Heterogeneity: Chi2 = 0.03, df = 1 (P = 0.87); I2 =0.0% Test for overall effect: Z = 3.74 (P = 0.00018) Test for subgroup differences: Not applicable

-10

-5

Favours IPC +

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0

5

10

Favours compression

30

Analysis 3.1. Comparison 3 IPC plus compression versus compression alone - sensitivity analysis, Outcome 1 Number healed in trial. Review:

Intermittent pneumatic compression for treating venous leg ulcers

Comparison: 3 IPC plus compression versus compression alone - sensitivity analysis Outcome: 1 Number healed in trial

Study or subgroup

IPC + compression

Compression

n/N

n/N

Alvarez 2012

22/25

16/27

38.0 %

1.49 [ 1.05, 2.10 ]

McCulloch 1994

12/12

8/10

22.8 %

1.24 [ 0.89, 1.75 ]

Schuler 1996

20/28

15/25

39.2 %

1.19 [ 0.80, 1.77 ]

65

62

100.0 %

1.31 [ 1.06, 1.63 ]

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

Total events: 54 (IPC + compression), 39 (Compression) Heterogeneity: Chi2 = 0.82, df = 2 (P = 0.66); I2 =0.0% Test for overall effect: Z = 2.48 (P = 0.013) Test for subgroup differences: Not applicable

0.02

0.1

1

Favours compression

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10

50

Favours IPC + comp

31

Analysis 3.2. Comparison 3 IPC plus compression versus compression alone - sensitivity analysis, Outcome 2 Rate of healing. Review:

Intermittent pneumatic compression for treating venous leg ulcers

Comparison: 3 IPC plus compression versus compression alone - sensitivity analysis Outcome: 2 Rate of healing

Study or subgroup

IPC + compression N

Alvarez 2012

25

Total (95% CI)

25

Mean Difference

Compression Mean(SD)[mm/day] 1.7 (12.5)

N 27

Mean(SD)[mm/day]

Weight

Mean Difference

100.0 %

0.90 [ -4.41, 6.21 ]

IV,Fixed,95% CI

IV,Fixed,95% CI

0.8 (5.4)

27

100.0 % 0.90 [ -4.41, 6.21 ]

Heterogeneity: not applicable Test for overall effect: Z = 0.33 (P = 0.74) Test for subgroup differences: Not applicable

-100

-50

0

Favours experimental

50

100

Favours control

Analysis 4.1. Comparison 4 IPC versus compression (bandage or stocking), Outcome 1 Number healed in trial. Review:

Intermittent pneumatic compression for treating venous leg ulcers

Comparison: 4 IPC versus compression (bandage or stocking) Outcome: 1 Number healed in trial

Study or subgroup

IPC alone

Compression alone

Risk Ratio MH,Random,95% CI

Risk Ratio MH,Random,95% CI

n/N

n/N

Dolibog 2013

5/22

8/48

1.36 [ 0.50, 3.70 ]

Rowland 2000

0/10

0/6

0.0 [ 0.0, 0.0 ]

0.5

0.7

Favours compression alone

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1.5

2

Favours IPC alone

32

Analysis 5.1. Comparison 5 Fast IPC versus Slow IPC, Outcome 1 Number healed in trial. Review:

Intermittent pneumatic compression for treating venous leg ulcers

Comparison: 5 Fast IPC versus Slow IPC Outcome: 1 Number healed in trial

Study or subgroup

Fast IPC

Slow IPC

n/N

n/N

Risk Ratio

Weight

Nikolovska 2005

45/52

32/52

100.0 %

1.41 [ 1.11, 1.79 ]

Total (95% CI)

52

52

100.0 %

1.41 [ 1.11, 1.79 ]

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

Total events: 45 (Fast IPC), 32 (Slow IPC) Heterogeneity: not applicable Test for overall effect: Z = 2.78 (P = 0.0054) Test for subgroup differences: Not applicable

0.1 0.2

0.5

Favours Slow IPC

1

2

5

10

Favours Fast IPC

APPENDICES Appendix 1. Search methods for the second update of this review (2011)

Electronic searches For an outline of the search methods used in second update of this review see Appendix 1. • Cochrane Wounds Group Specialised Register (searched 10 December 2010); • The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 4); • Ovid MEDLINE¬ (2007 to November Week 3 2010); • Ovid MEDLINE (In-Process & Other Non-Indexed Citations December 09, 2010); • Ovid EMBASE (2007 to 2010 Week 48); • EBSCO CINAHL (2007 to 3 December 2010) We used the following strategy to search the Cochrane Central Register of Controlled Trials (CENTRAL): #1 MeSH descriptor Intermittent Pneumatic Compression Devices explode all trees #2 pneumatic NEAR compression* #3 compression NEAR device* #4 flowtron or IPC #5 sequential NEAR compression* #6 (#1 OR #2 OR #3 OR #4 OR #5) #7 MeSH descriptor Leg Ulcer explode all trees #8 MeSH descriptor Varicose Ulcer explode all trees #9 leg NEXT ulcer* #10 venous NEXT ulcer* Intermittent pneumatic compression for treating venous leg ulcers (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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#11 stasis NEXT ulcer* #12 varicose NEXT ulcer* #13 (#7 OR #8 OR #9 OR #10 OR #11 OR #12) #14 (#6 AND #13) The search strategies for Ovid MEDLINE, Ovid EMBASE and EBSCO CINAHL can be found in Appendix 2, Appendix 3 and Appendix 4 respectively. We combined the Ovid MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision); Ovid format (Lefebvre 2009). We combined the Ovid EMBASE and EBSCO CINAHL searches with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (SIGN 2009). There were no restrictions on the basis of date or language of publication and translations of all relevant non-English language papers were obtained using local resources. Searching other resources We searched the bibliographies of all retrieved and relevant publications identified by these strategies for further studies.

Appendix 2. Ovid MEDLINE search strategy 1 exp Intermittent Pneumatic Compression Devices/ (401) 2 (pneumatic adj10 compression*).tw. (1004) 3 (compression adj10 device*).tw. (1634) 4 (flowtron or IPC).tw. (2080) 5 (sequential adj10 compression*).tw. (294) 6 or/1-5 (4483) 7 exp Leg Ulcer/ (17058) 8 (varicose ulcer* or venous ulcer* or leg ulcer* or stasis ulcer* or (lower extremit* adj ulcer*) or crural ulcer* or ulcus cruris).tw. (6906) 9 or/7-8 (18386) 10 6 and 9 (76) 11 randomized controlled trial.pt. (367527) 12 controlled clinical trial.pt. (87863) 13 randomi?ed.ab. (319269) 14 placebo.ab. (143982) 15 clinical trials as topic.sh. (168782) 16 randomly.ab. (189948) 17 trial.ti. (115063) 18 or/11-17 (862270) 19 exp animals/ not humans.sh. (3905320) 20 18 not 19 (792889) 21 10 and 20 (24)

Appendix 3. Ovid EMBASE search strategy 1 exp Intermittent Pneumatic Compression Devices/ (615) 2 (pneumatic adj10 compression*).tw. (1400) 3 (compression adj10 device*).tw. (2314) 4 (flowtron or IPC).tw. (3011) 5 (sequential adj10 compression*).tw. (419) 6 or/1-5 (6534) 7 exp Leg Ulcer/ (11720) 8 (varicose ulcer* or venous ulcer* or leg ulcer* or stasis ulcer* or (lower extremit* adj ulcer*) or crural ulcer* or ulcus cruris).tw. (9415) 9 or/7-8 (14902) 10 6 and 9 (102) 11 Randomized controlled trials/ (48928) Intermittent pneumatic compression for treating venous leg ulcers (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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12 Single-Blind Method/ (18016) 13 Double-Blind Method/ (114795) 14 Crossover Procedure/ (38308) 15 (random$ or factorial$ or crossover$ or cross over$ or cross-over$ or placebo$ or assign$ or allocat$ or volunteer$).ti,ab. (1307393) 16 (doubl$ adj blind$).ti,ab. (144629) 17 (singl$ adj blind$).ti,ab. (14210) 18 or/11-17 (1372939) 19 exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/ (20054892) 20 human/ or human cell/ (14578645) 21 and/19-20 (14531979) 22 19 not 21 (5522913) 23 18 not 22 (1184162) 24 10 and 23 (30)

Appendix 4. EBSCO CINAHL search strategy S23 S10 AND S22 S22 S11 or S12 or S13 or S14 or S15 or S16 or S17 or S18 or S19 or S20 or S21 S21 MH “Quantitative Studies” S20 TI placebo* or AB placebo* S19 MH “Placebos” S18 TI random* allocat* or AB random* allocat* S17 MH “Random Assignment” S16 TI randomi?ed control* trial* or AB randomi?ed control* trial* S15 AB ( singl* or doubl* or trebl* or tripl* ) and AB ( blind* or mask* ) S14 TI ( singl* or doubl* or trebl* or tripl* ) and TI ( blind* or mask* ) S13 TI clinic* N1 trial* or AB clinic* N1 trial* S12 PT Clinical trial S11 MH “Clinical Trials+” S10 S5 and S9 S9 S6 or S7 or S8 S8 lower extremity N3 ulcer* or AB lower extremity N3 ulcer* S7 TI (varicose ulcer* or venous ulcer* or leg ulcer* or foot ulcer* or (feet N1 ulcer*) or stasis ulcer* or crural ulcer*) or AB (varicose ulcer* or venous ulcer* or leg ulcer* or foot ulcer* or (feet N1 ulcer*) or stasis ulcer* or crural ulcer*) S6 (MH “Leg Ulcer+”) S5 S1 or S2 or S3 or S4 S4 TI ( flowtron or IPC ) or AB ( flowtron or IPC ) S3 TI sequential N3 compression or AB sequential N3 compression S2 TI compression N3 device* or AB compression N3 device* S1 TI pneumatic N3 compression or AB pneumatic N3 compression

Appendix 5. Risk of bias criteria

1. Was the allocation sequence randomly generated?

Low risk of bias The investigators describe a random component in the sequence generation process such as: referring to a random number table; using a computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots.

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High risk of bias The investigators describe a non-random component in the sequence generation process. Usually, the description would involve some systematic, non-random approach, for example: sequence generated by odd or even date of birth; sequence generated by some rule based on date (or day) of admission; sequence generated by some rule based on hospital or clinic record number.

Unclear Insufficient information about the sequence generation process to permit judgement of ‘Yes’ or ‘No’.

2. Was the treatment allocation adequately concealed?

Low risk of bias Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web-based and pharmacy-controlled randomisation); sequentially-numbered drug containers of identical appearance; sequentially-numbered, opaque, sealed envelopes.

High risk of bias Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.

Unclear Insufficient information to permit judgement of ‘Yes’ or ‘No’. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement, for example if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque and sealed.

3. Blinding was knowledge of the allocated interventions adequately prevented during the study?

Low risk of bias Any one of the following: • No blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding. • Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken. • Either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non-blinding of others unlikely to introduce bias.

High risk of bias Any one of the following: • No blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding. • Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken. • Either participants or some key study personnel were not blinded, and the non-blinding of others likely to introduce bias.

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Unclear Any one of the following: • Insufficient information to permit judgement of ‘Yes’ or ‘No’. • The study did not address this outcome.

4. Were incomplete outcome data adequately addressed?

Low risk of bias Any one of the following: • No missing outcome data. • Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias). • Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups. • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate. • For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size. • Missing data have been imputed using appropriate methods.

High risk of bias Any one of the following: • Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups. • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate. • For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size. • ‘As-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation. • Potentially inappropriate application of simple imputation.

Unclear Any one of the following: • Insufficient reporting of attrition/exclusions to permit judgement of ‘Yes’ or ‘No’ (e.g. number randomized not stated, no reasons for missing data provided). • The study did not address this outcome.

5. Are reports of the study free of suggestion of selective outcome reporting?

Low risk of bias Any of the following: • The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way. • The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon)

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High risk of bias Any one of the following: • Not all of the study’s pre-specified primary outcomes have been reported. • One or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified. • One or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect). • One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis. • The study report fails to include results for a key outcome that would be expected to have been reported for such a study. Unclear Insufficient information to permit judgement of ‘Yes’ or ‘No’. It is likely that the majority of studies will fall into this category.

6. Other sources of potential bias:

Low risk of bias The study appears to be free of other sources of bias. High risk of bias There is at least one important risk of bias. For example, the study: • had a potential source of bias related to the specific study design used; or • stopped early due to some data-dependent process (including a formal-stopping rule); or • had extreme baseline imbalance; or • has been claimed to have been fraudulent; or • had some other problem. Unclear There may be a risk of bias, but there is either: • insufficient information to assess whether an important risk of bias exists; or • insufficient rationale or evidence that an identified problem will introduce bias.

WHAT’S NEW Last assessed as up-to-date: 1 April 2014.

Date

Event

Description

30 April 2014

New citation required and conclusions have changed

The reviewers’ conclusions were updated and changed.

30 April 2014

New search has been performed

Third update. New searches carried out. Two new trials included (Alvarez 2012; Dolibog 2013). Risk of bias tables updated for all included studies. New author joined the team

Intermittent pneumatic compression for treating venous leg ulcers (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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HISTORY Protocol first published: Issue 1, 2000 Review first published: Issue 4, 2001

Date

Event

Description

12 January 2011

New citation required but conclusions have not New author added to the review team for this update. changed

4 January 2011

New search has been performed

Second update, new searches carried out no new trials identified. Risk of bias table completed for all included studies

10 November 2009

Amended

Contact details updated.

2 September 2008

Amended

Converted to new review format.

5 February 2008

New citation required and conclusions have changed

Substantive amendment For this first update new searches were carried out in December 2007. 34 citations were identified, of which 3 (Kumar 2001; Nikolovska 2002; Nikolovska 2005) were included, 25 citations to 23 studies did not meet the inclusion criteria for this review and have been added to the Table of Excluded studies. The reviewers’ conclusions were changed.

CONTRIBUTIONS OF AUTHORS Initial review: RM initiated the review, checked search results for relevant studies, extracted data from included trials, drafted the review. KV commented on the draft review. EAN checked the relevant studies for inclusion, checked the data extraction and commented on the draft review. First update and second update: EAN initiated the update, checked search results for relevant studies, extracted data from included trials, drafted the review and the review updates. KT checked search results for relevant studies for the second update and undertook the risk of bias assessment on all the included studies. Third update: AH checked search results for relevant studies, extracted data from included trials, updated existing risk of bias tables and drafted the review update. EAN commented on the draft review.

Intermittent pneumatic compression for treating venous leg ulcers (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Contributions of editorial base:

Nicky Cullum: Approved the final review and review update prior to submission. Sally Bell-Syer: coordinated the editorial process. Advised on methodology, interpretation and content. Edited and copy edited the review and the updated review. Ruth Foxlee: designed the search strategy, ran the searches and edited the search methods section for the update.

DECLARATIONS OF INTEREST None

SOURCES OF SUPPORT Internal sources • • • • •

University of Southampton Hospitals Trust NHS, UK. Department of Health Sciences, The University of York, UK. Department of Vascular Surgery, Bradford Hospitals NHS Trust, UK. School of Health Studies, University of Bradford, UK. School of Healthcare, University of Leeds, UK.

External sources • NHS Health Technology Assessment Programme, UK. • The National Institute for Health Research (NIHR) is the sole funder of the Cochrane Wounds Group, UK.

INDEX TERMS Medical Subject Headings (MeSH) ∗ Bandages; ∗ Intermittent Pneumatic Compression Devices; Air; Randomized Controlled Trials as Topic; Stockings, Compression; Varicose Ulcer [∗ therapy]; Wound Healing

MeSH check words Humans

Intermittent pneumatic compression for treating venous leg ulcers (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Intermittent pneumatic compression for treating venous leg ulcers.

Intermittent pneumatic compression (IPC) is a mechanical method of delivering compression to swollen limbs that can be used to treat venous leg ulcers...
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