physical exercise for the treatment of non-ulcerated...

Physical exercise for the treatment of non-ulcerated chronicvenous insufficiency (Protocol)

Araujo DN, Ribeiro CTD, Maciel ACC, Bruno SS, Fregonezi GAF, Dias FAL

This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The CochraneLibrary 2013, Issue 7

http://www.thecochranelibrary.com

Physical exercise for the treatment of non-ulcerated chronic venous insufficiency (Protocol)

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iPhysical exercise for the treatment of non-ulcerated chronic venous insufficiency (Protocol)


[Intervention Protocol]

Physical exercise for the treatment of non-ulcerated chronicvenous insufficiency

Diego N Araujo1, Cibele TD Ribeiro1, Alvaro CC Maciel2, Selma S Bruno2, Guilherme AF Fregonezi2, Fernando AL Dias3

1Graduate Program in Physiotherapy, Federal University of Rio Grande do Norte, Natal, Brazil. 2Department of Physical Therapy,Federal University of Rio Grande do Norte, Natal, Brazil. 3Department of Physiology, Federal University of Paraná, Curitiba, Brazil

Contact address: Fernando AL Dias, Department of Physiology, Federal University of Paraná, Centro Politécnico, Jardim das Américas,Caixa Postal 19031, Curitiba, Paraná, 81531-980, Brazil. [email protected].

Editorial group: Cochrane Peripheral Vascular Diseases Group.Publication status and date: New, published in Issue 7, 2013.

Citation: Araujo DN, Ribeiro CTD, Maciel ACC, Bruno SS, Fregonezi GAF, Dias FAL. Physical exercise for the treatment ofnon-ulcerated chronic venous insufficiency. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD010637. DOI:10.1002/14651858.CD010637.


A B S T R A C T

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess and summarise the existing clinical evidence on the effectiveness and safety of physical exercise programmes for the treatmentof non-ulcerated chronic venous insufficiency (CVI).

B A C K G R O U N D

Description of the condition

Chronic venous disease (CVD) is defined as long-standing mor-phological and functional venous abnormalities that may or maynot be symptomatic. This condition can be present in a less se-vere manifestation such as telangiectasia (small dilated blood ves-sels) or may progress to varicose veins and even skin ulceration(Beebe-Dimmer 2005; Staffa 2002). Chronic venous insufficiency(CVI) is often clinically defined as functional abnormalities of thevenous system resulting in changes in skin and subcutaneous tis-sue (Eklof 2004; Evans 1999). CVI is more common in the el-derly population (De Araujo 2003; Wipke-Tevis 2000) and is themain cause of venous ulceration (De Araujo 2003). The age-ad-justed prevalence of CVI is estimated to be around 9% in men and7% in women (Evans 1999) and it constitutes an economic bur-

den to public health, especially when venous ulceration is present(De Araujo 2003; Wipke-Tevis 2000). Risk factors associated withCVI include family history, female gender, number of pregnan-cies, old age, lifestyle and occupational activities. Its developmentis thought to be related to sustained erect posture (Beebe-Dimmer2005; Staffa 2002).Physical alterations related to CVI occur mainly in the lower limbs,such as oedema, hyperpigmentation, eczema and lipodermatoscle-rosis. These alterations are the consequence of valvular insuffi-ciency or venous obstruction, resulting in long-term venous hy-pertension due to venous stasis in the lower limbs. Foot, calf andthigh muscle pump function may be impaired in patients withCVI (Meissner 2005). This contributes to disease progression be-cause these muscles are the strongest power source for venous re-turn in lower limbs (Goldman 1989).The diagnosis of CVI is primarily based on clinical examina-tion and patient history. There is a widely accepted international

1Physical exercise for the treatment of non-ulcerated chronic venous insufficiency (Protocol)


mailto:[email protected]

classification, CEAP (Clinical, Etiology, Anatomic, Pathophysi-ology), that was developed to help the reporting and diagnosingof CVD (Eklof 2004) (Table 1). Additional specific tests are alsoused to make differential diagnosis, such as venous duplex imag-ing, plethysmography, phlebography and the ankle-brachial index(ABI) test (Collins 2010; Eberhardt 2005). Common symptomsare itching and burning sensations in the lower limbs, and pain,causing a great impact on the quality of life (QoL) of individualswith this disease (Duque 2005).

Description of the intervention

Exercise modalities have been prescribed for the treatment of pe-ripheral vascular disease (PVD) from different aetiologies. Datasupport the use of therapeutic exercise for the treatment of periph-eral arterial disease (PAD) (Rooke 2011); however, exercise pre-scription for CVI is not very well established (Davies 2008). Over-all, physical activity has been associated with a marked decreasein cardiovascular mortality and all-cause mortality (Nocon 2008).Prescribed exercise has been recommended for primary preventionof cardiovascular disease and its effects include, but are not limitedto: glycaemic control; increase in high density lipoprotein (HDL)cholesterol; reduction in blood pressure; weight loss; reduction ofdepression, anxiety and psychological stress, as well as an increasein cardiorespiratory fitness and muscle strength (Metkus 2010).In the clinical setting, exercises to increase ankle joint mobilityand exercises prescribed for flexibility and strengthening of calfmuscles have been recommended in patients with CVI aiming toimprove muscle pump function and, therefore, haemodynamics.Furthermore, CVI is highly prevalent in the elderly (Brand 1988;Heit 2001) and the effects and safety of exercise prescription onCVI have not been systematically reviewed.

How the intervention might work

Studies have shown that the application of a physical exercise pro-gramme may have a number of benefits: reducing oedema of thelower limbs, improving haemodynamic performance of the calfmuscle through strengthening of these muscles, improvement incardiorespiratory fitness, in turn improving functional capacityand QoL (Padberg 2004; Quilici 2009). Exercise programmes usu-ally consist of stretching and strengthening of lower limb musclesalongside aerobic exercises aimed to improve venous return, suchas walking. Even very small movements of the lower limbs maypromote important pumping action of the venous blood (Bergan2006). Researchers suggest that treatments which aim to increasethe movement of the ankle joint, with consequent strengtheningof the calf muscle pump, improve its function through an increaseof the ejection fraction and decrease of the residual fraction in theearly stages of CVI; this may be useful to prevent disease progres-sion and its consequences (Yang 1999).

Why it is important to do this review

Chronic venous insufficiency is a highly prevalent PVD. The dis-ease can progress to a phase where subcutaneous alterations be-come evident and develop into a venous leg ulcer, which is achronic hard-to-heal wound. Interventions that can improve thedisease or reduce its progress are desirable. Therapeutic exercise,especially when prescribed in association with therapeutic com-pression, is usually indicated for CVI patients. However, there isno up-to-date systematic review available to assess the effects ofexercise on non-ulcerated CVI. This present review will help todetermine the safety and possible benefits of exercise prescriptionfor the treatment of non-ulcerated CVI. If effective, physical exer-cise may be considered a low-cost treatment regime to be adoptedamong healthcare providers for patients with CVI to treat and pre-vent disease progression. The effects of exercise on chronic venousleg ulcer healing will not be assessed in this review.

O B J E C T I V E S

To assess and summarise the existing clinical evidence on the effec-tiveness and safety of physical exercise programmes for the treat-ment of non-ulcerated chronic venous insufficiency (CVI).

M E T H O D S

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs) where anexercise programme was used as the main or adjunctive treatmentfor non-ulcerated chronic venous insufficiency (CVI).

Types of participants

We will include clinical studies involving patients with non-ulcer-ated CVI regardless of sex and ethnicity. We will consider the CVIdiagnosis given by trial authors; therefore, classification of CVImay differ between studies where some may only include CEAP 3-5 while others may include less severe clinical manifestation suchas CEAP 2 and define it as CVI. If the exercise treatment was car-ried out in patients with CVI and leg ulcers are present, we will notinclude the study. This is because the major outcomes would bedifferent and difficult to assess within the same review. However,if both non-ulcerated and ulcerated CVI participants are includedin studies and the outcomes are reported separately, such studieswill be included. As different main outcomes are relevant to ul-cerated CVI (for example, percentage reduction in ulcer area or



percentage of fully healed ulcers), the effects of exercise on venousleg ulcer healing will not be assessed in this review. Studies wherethe exercise treatment was investigated in patients with peripheralartery disease (PAD) will not be included, unless the results arereported separately by groups.

Types of interventions

We will compare supervised or unsupervised prescribed exerciseprogrammes as the main or adjunctive treatment for patients withnon-ulcerated CVI with either the same treatment protocol with-out exercise or without treatment.

Types of outcome measures

Primary outcomes

1) Intensity of disease signs and symptoms measured by a validatedinstrument such as the Venous Clinical Severity Score (Rutherford2000; Vasquez 2010) (See Table 2).2) Ejection fraction measured by air plethysmography or duplexultrasonography.3) Incidence of venous leg ulcer.

Secondary outcomes

1) Quality of life (QoL) measured by validated instruments (as theVEINES-QOL/Sym or the SF-36 questionnaires).2) Exercise capacity as measured by an objective test, such as thesix-minute walk test or maximal distance walked on treadmill.3) Muscle strength measured by dynamometry.4) Incidence of surgical intervention to treat symptoms related toCVI.5) Ankle joint mobility.

Search methods for identification of studies

Electronic searches

The Cochrane Peripheral Vascular Diseases Group Trials SearchCo-ordinator (TSC) will search the Specialised Register and theCochrane Central Register of Controlled Trials (CENTRAL),part of The Cochrane Library, (www.thecochranelibrary.com). SeeAppendix 1 for details of the search strategy which will be used tosearch CENTRAL. The Specialised Register is maintained by theTSC and is constructed from weekly electronic searches of MED-LINE, EMBASE, CINAHL, AMED, and through handsearchingrelevant journals. The full list of the databases, journals and con-ference proceedings which have been searched, as well as the searchstrategies used are described in the Specialised Register section of

the Cochrane Peripheral Vascular Diseases Group module in TheCochrane Library (www.thecochranelibrary.com).The following trial databases will be searched by the TSC fordetails of ongoing and unpublished studies:World Health Organization International Clinical Trials Registryhttp://apps.who.int/trialsearch/ClinicalTrials.gov http://clinicaltrials.gov/Current Controlled Trials http://www.controlled-trials.com/

Searching other resources

We will search the bibliographies of relevant publications identi-fied by the above strategies for further studies. We will attempt tocontact researchers to obtain additional information when needed.

Data collection and analysis

Selection of studies

Two review authors (DA and FD) will independently screen thetitles and abstracts of the studies identified by the search strategyagainst the inclusion criteria. We will obtain full versions of articlesthat appear to fulfil the inclusion criteria for further assessment. Ifnecessary, another review author (GF) will evaluate any discrep-ancies and will advise in case of disagreement. We will record allreasons for exclusion.

Data extraction and management

Two review authors (DA and FD), working independently, willextract data, summarise details of trials using a standard data ex-traction sheet and enter data into RevMan 5.2 (RevMan 2012).We will resolve any discrepancies by discussion with a third reviewauthor (GF). Where reported, we will extract the following infor-mation according to methods described in the Cochrane Handbookfor Systematic Reviews of Interventions (Higgins 2011a):

• country of origin;• study authors and year of publication;• publication type;• study design;• care setting;• type of participants;• method of recruitment of participants;• types of outcome measures;• unit of investigation (per patient, cluster);• number of participants randomised to each trial;• eligibility criteria and key baseline participant data (gender,

age, ethnicity, disease duration, prevalence of co-morbiditiessuch as diabetes and peripheral artery disease);

• details of the treatment regimen received by each group;• type of exercise;



• details of any co-interventions;• primary and secondary outcome(s) with definitions;• outcome data for primary and secondary outcomes (by

group);• overall sample size and methods used to estimate statistical

power (relates to the target number of participants to berecruited, the clinical difference to be detected and the ability ofthe trial to detect this difference);

• duration of treatment period;• duration of follow-up;• number of withdrawals (by group with reasons);• statistical methods used for data analysis;• risk of bias criteria (sequence generation, allocation

concealment, blinding, incomplete outcome data, selectiveoutcome reporting);

• adverse events;• source of funding.

Assessment of risk of bias in included studies

Two authors (DA and FD) will independently assess each includedstudy using The Cochrane Collaboration’s tool for assessing riskof bias. This tool addresses six specific domains, namely randomsequence generation, allocation concealment, blinding of partici-pants and personnel, incomplete outcome data, selective outcomereporting and other sources of bias (see Appendix 2 for detailsof criteria on which the judgement will be based). We will assessblinding and completeness of outcome data for each outcome sep-arately. We will complete a ’Risk of bias’ table for each eligiblestudy and classify these as having either high, low or unclear risk,according to the methods described in Chapter 8 of the CochraneHandbook for Systematic Reviews of Interventions (Higgins 2011b).We will discuss any disagreement amongst all authors to achievea consensus.We will present our assessment using a ’Risk of bias’ summaryfigure, which presents all of the judgments in a cross-tabulationof study by entry. This display of internal validity indicates theweight the reader may give the results of each study.We will classify trials as being at high risk of bias if they are ratedhigh for any of three key criteria (randomisation sequence, alloca-tion concealment and blinded outcome assessment).

Measures of treatment effect

We will perform data analysis according to the guidelines of TheCochrane Collaboration. One review author (DA) will enter quan-titative data into Review Manager 5 (RevMan) (RevMan 2012),and these will be checked by another review author (FD), and anal-ysed using The Cochrane Collaboration’s associated software. Wewill present the outcome results for each trial with 95% confidenceintervals (CI). We will report estimates for continuous outcomes(such as ejection fraction, disease severity questionnaire scores) as

mean difference (MD) and overall effect size (with 95% CI cal-culated) and dichotomous outcomes (such as ulcer incidence) asrisk ratio (RR).

Unit of analysis issues

We will treat the number of individual participants as the unit ofanalysis in this review. We will include cluster-randomised trialsin the analysis. For cluster-randomised trials, we will adjust resultswhen the unit of analysis in the trial is presented as the total numberof individual participants instead of number of clusters. We willadjust the results using the mean cluster size and intracluster corre-lation coefficient (Higgins 2011c). For meta-analysis, we will pooldata to individually-randomised trials using the generic inverse-variance method as described in Chapter 16.3 of the CochraneHandbook for Systematic Reviews of Interventions (Higgins 2011e).

Dealing with missing data

In the case of missing data, we will contact the original investigatorsto request these data whenever possible. If a trial does not specifyparticipant group number prior to dropout, we will present onlycomplete case analysis for primary and secondary outcomes.

Assessment of heterogeneity

We will pool data for meta-analysis using RevMan (RevMan2012). We will consider clinical heterogeneity (that is where trialsappear similar in terms of level of participants, intervention typeand duration and outcome type) and statistical heterogeneity. Wewill assess statistical heterogeneity using the Chi² test (a signifi-cance level of P < 0.10 is considered to indicate significant hetero-geneity) in conjunction with the I² statistic (Higgins 2003). TheI² statistic examines the percentage of total variation across trialsdue to heterogeneity rather than variation due to chance (Higgins2003). Heterogeneity will be categorised as follows: I² values ≤

40% indicate a low level of heterogeneity and ≥ 75% to representvery high heterogeneity (Higgins 2011c).

Assessment of reporting biases

If sufficient studies (more than 10) are identified, an attempt willbe made to examine for publication bias using funnel plots as de-scribed in the Cochrane Handbook for Systematic Reviews of Inter-ventions (Higgins 2011d). If asymmetry is present, we will explorepossible causes including publication bias, poor methodologicalquality and true heterogeneity.

Data synthesis

We will present a narrative overview of the combined studies witha meta-analysis of outcome data using RevMan (RevMan 2012)where appropriate. The decision to include studies in a meta-



analysis will depend on the availability of treatment effect dataand assessment of heterogeneity. For comparisons where there isno apparent clinical heterogeneity and the I2 value is ≤ 40%, wewill apply a fixed-effect model. Where there is no apparent clinicalheterogeneity and the I2 value is > 40%, we will apply a random-effects model. However, we will not pool data where heterogeneityis very high (I2 values ≥ 75%).

Subgroup analysis and investigation of heterogeneity

We plan to carry out subgroup analysis according to differencesin the following variables: studies that report the treatment in thepresence or absence of compression therapy independent of type(elastic or non-elastic) or level (moderate or high) of compression.

Sensitivity analysis

If sufficient trials are identified, we plan to conduct sensitivityanalyses in order to explore the influence on the results of thefollowing factors: assessor blinding (high risk of bias versus low riskof bias), analysis method (we will carry out a sensitivity analysisto explore the effects of fixed-effect or random-effects analyses foroutcomes with statistical heterogeneity).

Summary of findings table

The review authors (DA, FD, CR) will grade the quality of theevidence for each primary outcome using four levels of quality:high, moderate, low and very low (Schünemann 2011a). We planto record the quality in a ’Summary of findings’ table using theGRADE system as described in the Cochrane Handbook for System-atic Reviews of Interventions (Schünemann 2011b) for the primaryoutcomes. Quality will be based on the following factors.1. Limitations in the design and implementation of available stud-ies suggesting high likelihood of bias.

2. Indirectness of evidence (indirect population, intervention, con-trol, outcomes).

3. Unexplained heterogeneity or inconsistency of results (includ-ing problems with subgroup analyses).

4. Imprecision of results (wide confidence intervals).

5. High probability of publication bias.

A C K N O W L E D G E M E N T S

The authors would like to thank Dr Marlene Stewart (ManagingEditor) and Dr Cathryn Broderick (Assistant Managing Editor)for their assistance in the development of the protocol. We thankThiago Nunes for assistance in the initial draft of the protocol.

R E F E R E N C E S

Additional references

Beebe-Dimmer 2005

Beebe-Dimmer JL, Pfeifer JR, Engle JS, Schottenfeld D.The epidemiology of chronic venous insufficiency andvaricose veins. Annals of Epidemiology 2005;15(3):175–84.

Bergan 2006

Bergan JJ, Schmid-Schonbein GW, Smith PDC, NicolaidesAN, Boisseau MR, Eklof B. Mechanisms of disease -Chronic venous disease. The New England Journal ofMedicine 2006;355(5):488–98.

Brand 1988

Brand FN, Dannenberg AL, Abbot RD, Kannel WB. Theepidemiology of varicose veins: the Framingham study.American Journal of Preventive Medicine 1988;4(2):96–101.

Collins 2010Collins L, Seraj S. Diagnosis and treatment of venous ulcers.American Family Physician 2010;81(8):989–96.

Davies 2008

Davies J, Bull R, Farrelly I, Wakelin M. Improving the calfpump using home-based exercises for patients with chronicvenous diseases. Wounds UK 2008;4(3):48–58.

De Araujo 2003

De Araujo T, Valencia I, Federman DG, Kirsner RS.Managing the patient with venous ulcers. Annals Internal

Medicine 2003;138(4):326–34.

Duque 2005

Duque MI, Yosipovitch G, Chan YH, Smith R, Levy P.Itch, pain, and burning sensation are common symptomsin mild to moderate chronic venous insufficiency with animpact on quality of life. Journal of the American Academy of

Dermatology 2005;53(3):504–8.

Eberhardt 2005

Eberhardt RT, Raffetto JD. Chronic venous insufficiency.Circulation 2005;111(18):2398-409.

Eklof 2004

Eklof B, Rutherford RB, Bergan JJ, Carpentier PH,Gloviczki P, Kistner RL, et al.Revision of the CEAPclassification for chronic venous disorders: consensusstatement. Journal Vascular Surgery 2004;40(6):1248–52.

Evans 1999

Evans CJ, Fowkes FGR, Ruckley CV, Lee AJ. Prevalence ofvaricose veins and chronic venous insufficiency in men andwomen in the general population: Edinburgh Vein Study.



Journal of Epidemiology and Community Health 1999;53:149–53.

Goldman 1989

Goldman MP, Fronek A. Anatomy and pathophysiology ofvaricose veins. Journal of Dermatologic Surgery Oncology

1989;15(2):138–45.

Heit 2001

Heit JA, Rooke TW, Silverstein MD, Mohr DN, LohseCM, Petterson TM, et al.Trends in the incidence of venousstasis syndrome and venous ulcer: a 25-year population-based study. Journal of Vascular Surgery 2001;33(5):1022–7.

Higgins 2003Higgins JPT, Thompson SG, Deeks JJ, Altman DG.Measuring inconsistency in meta-analyses. BMJ 2003;327:557–60.

Higgins 2011aHiggins JPT, Deeks JJ (editors). Chapter 7: Selectingstudies and collecting data. In: Higgins JPT, Green S(editors). Cochrane Handbook for Systematic Reviewsof Interventions Version 5.1.0 [updated March 2011].The Cochrane Collaboration, 2011. Available fromwww.cochrane-handbook.org.

Higgins 2011bHiggins JPT, Altman DG, Sterne JAC (editors). Chapter8: Assessing risk of bias in included studies. In: HigginsJPT, Green S (editors). Cochrane Handbook for SystematicReviews of Interventions Version 5.1.0 [updated March2011]. The Cochrane Collaboration, 2011. Available fromwww.cochrane-handbook.org.. Chichester: John Wiley &Sons.

Higgins 2011cDeeks JJ, Higgins JPT, Altman DG (editors). Chapter 9:Analysing data and undertaking meta-analyses. In: HigginsJPT, Green S (editors). Cochrane Handbook for SystematicReviews of Interventions Version 5.1.0 [updated March2011]. The Cochrane Collaboration, 2011. Available fromwww.cochrane-handbook.org.

Higgins 2011dSterne JAC, Egger M, Moher D (editors). Chapter 10:Addressing reporting biases. In: Higgins JPT, Green S(editors). Cochrane Handbook for Systematic Reviewsof Interventions Version 5.1.0 [updated March 2011].The Cochrane Collaboration, 2011. Available fromwww.cochrane-handbook.org. Chichester: John Wiley &Sons.

Higgins 2011eHiggins JPT, Deeks JJ, Altman DG (editors). Chapter16: Special topics in statistics. In: Higgins JPT, Green S(editors). Cochrane Handbook for Systematic Reviewsof Interventions Version 5.1.0 [updated March 2011].The Cochrane Collaboration, 2011. Available fromwww.cochrane-handbook.org.

Meissner 2005

Meissner MH. Lower extremity venous anatomy. Seminarsin Interventional Radiology 2005;22(3):147–56.

Metkus 2010

Metkus TS Jr, Baughman KL, Thompson PD. Exerciseprescription and primary prevention of cardiovasculardisease. Circulation 2010;121(123):2601–4.

Nocon 2008

Nocon M, Hiemann T, Muller-Riemenschneider F, ThalauF, Roll S, Willich SN. Association of physical activity withall-cause and cardiovascular mortality: a systematic reviewand meta-analysis. European Journal of CardiovascularPrevention and Rehabilitation 2008;15(3):239–46.

Padberg 2004

Padberg FT Jr, Johnston MV, Sisto SA. Structured exerciseimproves calf muscle pump function in chronic venousinsufficiency: A randomized trial. Journal of VascularSurgery 2004;39(1):79–87.

Quilici 2009Quilici BCE, Gildo C Jr, De Godoy JMP, Quilici BS,Augusto CR. Comparison of reduction of edema after restand after muscle exercises in treatment of chronic venousinsufficiency. International Archives of Medicine 2009;2(18):1–5.

RevMan 2012

The Nordic Cochrane Centre, The Cochrane Collaboration.Review Manager (Revman). 5.2. Copenhagen: The NordicCochrane Centre, The Cochrane Collaboration, 2012.

Rooke 2011

Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA,Findeiss LK, et al.2011 ACCF/AHA Focused update of theguideline for the management of patients with peripheralartery disease (updating the 2005 guideline): a report ofthe American College of Cardiology Foundation/AmericanHeart Association Task Force on practice guidelines.Circulation 2011;124(18):2020–45.

Rutherford 2000

Rutherford RB, Padberg FT, Comerota AJ, Kistner RL,Meissner MH, Moneta GL. Venous severity scoring:An adjunct to venous outcome assessment. Journal ofVascular Surgery 2000;31:1307–12. [DOI: 10.1067/mva.2000.107094]

Schünemann 2011aSchünemann HJ, Oxman AD, Higgins JPT, Vist GE,Glasziou P, Guyatt GH on behalf of the CochraneApplicability and Recommendations Methods Group andthe Cochrane Statistical Methods Group. Chapter 11:Presenting results and ‘Summary of findings’ tables. In:Higgins JPT, Green S (editors). Cochrane Handbookfor Systematic Reviews of Interventions Version 5.1.0[updated March 2011]. The Cochrane Collaboration,2011. Available from www.cochrane-handbook.org.

Schünemann 2011bSchünemann HJ, Oxman AD, Vist GE, Higgins JPT,Deeks JJ, Glasziou P, et al.Chapter 12: Interpreting resultsand drawing conclusions. In: Higgins JPT, Green S(editors). Cochrane Handbook for Systematic Reviewsof Interventions Version 5.1.0 [updated March 2011].



The Cochrane Colaboration, 2011. Available fromwww.cochrane-handbook.org.

Staffa 2002Staffa R. Chronic venous insufficiency - epidemiology.Bratislavske Lekarske Listy 2002;103(4-5):166–8.

Vasquez 2010

Vasquez MA, Rabe E, McLafferty RB, Shortell CK, MarstonWA, Gillespie D, et al.Revision of the venous clinicalseverity score:Venous outcomes consensus statement:Special communication of the American Venous ForumAd Hoc Outcomes Working Group. Journal of VascularSurgery 2010; Vol. 52:1387–96. [DOI: 10.1016/

j.jvs.2010.06.161]

Wipke-Tevis 2000Wipke-Tevis DD, Rantz MJ, Mehr DR, Popejoy L, PetroskiG, Madsen R, et al.Prevalence, incidence, management, andpredictors of venous ulcers in the long-term-care populationusing the MDS. Advances in Skin and Wound Care 2000;13(5):218–24.

Yang 1999Yang D, Vandogen YK, Stacey MC. Effect of exercise oncalf muscle pump function in patients with chronic venousdisease. British Journal of Surgery 1999;86:338–41. [DOI:10.1046/j.1365-2168.1999.00993.x]

∗ Indicates the major publication for the study

A D D I T I O N A L T A B L E S

Table 1. CEAP Classification of Chronic Venous Disease

Classification Description/Definition

Clinical

0 no visible or palpable signs of venous disease

1 telangiectases or reticular veins

2 varicose veins

3 edema

4a pigmentation or eczema

4 lipodermatosclerosis or atrophie blanchie

5 healed venous ulcer

6 active venous ulcer

S symptomatic, including ache, pain, tightness, skin irritation, heaviness, muscle cramp, and other complaintsattributable to venous dysfunction

A asymptomatic

Etiologic

Ec congenital (present since birth)

Ep primary

Es secondary (post-thrombotic, traumatic)



Table 1. CEAP Classification of Chronic Venous Disease (Continued)

En no venous cause identified

Anatomic distribution

As superficial (great and short saphenous veins)

Ap perforator (thigh and leg perforating veins)

Ad deep (cava, iliac, gonadal, femoral, profunda, popliteal, tibial, and muscular veins)

An no venous location identified

Pathophysiological

Pr reflux (axial and perforating veins)

Po obstruction (acute and chronic)

Pr,o combination of both reflux and obstruction (valvular dysfunction and thrombus)

Pn no venous pathophysiology identified

Table 2. Venous Clinical Severity Score

Clinical descriptor Absent (0) Mild (1) Moderate (2) Severe (3)

Pain None Occasional Daily not limiting Daily limiting

Varicose veins None Few Calf or thigh Calf and thigh

Venous oedema None Foot and ankle Below knee Knee and above

Skin pigmentation None Limited perimalleolar Diffuse lower 1/3 calf Wider above lower 1/3 calf

Inflammation None Limited perimalleolar Diffuse lower 1/3 calf Wider above lower 1/3 calf

Induration None Limited perimalleolar Diffuse lower 1/3 calf Wider above lower 1/3 calf

No. active ulcers None 1 2 3 or more

Ulcer duration None < 3 mo 3 - 12 mo > 1 y

Active ulcer size None < 2 cm 2 - 6 cm > 6 cm

Compression therapy None Intermittent Most days Fully comply

cm: centimetre



mo: monthsNo.: numbery: year

A P P E N D I C E S

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Varicose Veins] explode all trees#2 (varicos* near/3 (vein* or veno* or saphenous))#3 (tortu* near/3 (vein* or veno* or saphenous))#4 (incomp* near/3 (vein* or veno* or saphenous or valv*))#5 (insuffic* near/3 (vein* or veno* or saphenous))#6 ((saphenous or vein* or veno*) near/3 reflux)#7 MeSH descriptor: [Venous Insufficiency] explode all trees#8 CVI#9 MeSH descriptor: [Leg] explode all trees and with qualifiers: [Blood supply - BS]#10 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9#11 MeSH descriptor: [Exercise] explode all trees#12 MeSH descriptor: [Exercise Therapy] explode all trees#13 MeSH descriptor: [Physical Exertion] this term only#14 MeSH descriptor: [Sports] explode all trees#15 MeSH descriptor: [Exercise Movement Techniques] explode all trees#16 MeSH descriptor: [Locomotion] explode all trees#17 MeSH descriptor: [Leisure Activities] this term only#18 MeSH descriptor: [Fitness Centers] this term only#19 MeSH descriptor: [Physical Exertion] this term only#20 (physical near/3 (exertion or endurance or therap* or conditioning or activit* or fitness)):ti,ab,kw#21 exercis*#22 (fitness near/3 (intervention* or protocol* or program* or therap* or activit* or regim* or centre* or center*)):ti,ab,kw#23 activit*#24 (walk* or run* or treadmill or aerobic or swim* or danc*):ti,ab,kw#25 kinesiotherap*:ti,ab,kw#26 ((endurance or aerobic or cardio*) near/3 (fitness or train* or intervention* or protoco* or program* or therap* or activit* orregim*)):ti,ab,kw#27 train*#28 #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27#29 #10 and #28 in Trials



Appendix 2. The Cochrane Collaboration’s tool for assessing risk of bias

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; usinga computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots.

High risk of bias

The investigators describe a non-random component in the sequence generation process. Usually, the description would involve somesystematic, non-random approach, for example: sequence generated by odd or even date of birth; sequence generated by some rulebased 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 low or high risk of bias.

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 equivalentmethod, 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 allocationbased on: using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriatesafeguards (e.g. if envelopes were unsealed or non opaque or not sequentially numbered); alternation or rotation; date of birth; caserecord number; any other explicitly unconcealed procedure.

Unclear

Insufficient information to permit judgement of low or high risk of bias. This is usually the case if the method of concealment is notdescribed 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.

Unclear

Any one of the following:• Insufficient information to permit judgement of low or high risk of bias.• 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 low or high risk of bias (e.g. number randomised 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 thereview 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 thatwere pre-specified (convincing text of this nature may be uncommon).

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. sub scales) 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 low or high risk of bias. 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• 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.



C O N T R I B U T I O N S O F A U T H O R S

Diego Araujo: Developed the first draft of the protocol; approved the final version of the protocol prior to submission and made anintellectual contribution to the protocol.

Cibele Ribeiro: Conceived the review question; advised and developed the first draft of the protocol; approved the final version of theprotocol prior to submission and made an intellectual contribution to the protocol.

Álvaro Maciel: Made an intellectual contribution to the protocol and approved the final version of the protocol prior to submission.

Selma Bruno: Made an intellectual contribution to the protocol and approved the final version of the protocol prior to submission.

Guilherme Fregonezi: Made an intellectual contribution to the protocol and approved the final version of the protocol prior tosubmission.

Fernando Dias: Conceived the review question; advised, developed and coordinated the first draft of the protocol; approved the finalversion of the protocol prior to submission and made an intellectual contribution to the protocol.

D E C L A R A T I O N S O F I N T E R E S T

The authors report that this work was partially supported by the grant from the Ministry of Science and Technology and NationalCouncil for Scientific and Techological Development (CNPq)- UNIVERSAL 2010, Brazil and by the grant from FAPERN and CT-INFRA intermediated by MCT/CNPq - Grant PPP 2009, Brazil.

S O U R C E S O F S U P P O R T

Internal sources

• No sources of support supplied

External sources

• Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.The PVD Group editorial base is supported by the Chief Scientist Office

• FAPERN and CT-INFRA intermediated by MCT/CNPq - Grant PPP 2009, Brazil.Financial support

• Ministry of Science and Technology and National Council for Scientific and Techological Development (CNPq)- UNIVERSAL2010, Brazil.Financial support



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