Compression stockings for the treatment of post-thrombotic syndrome Protocol information

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1 Compression stockings for the treatment of post-thrombotic syndrome Protocol information Authors Christopher F Berntsen 1, Annette Kristiansen 1, Elie A. Akl 2, Per Olav Vandvik 1 1 Department of Internal Medicine, Sykehuset Innlandet Hospital Trust 2 Department of Internal Medicine, Americal University of Beirut Contact person Christopher F Berntsen Background It has been reported that 20-50% of patients having suffered a deep vein thrombosis (DVT) develop post-thrombotic syndrome (PTS), which consists in pain, feeling of heaviness, cramps or itching in the leg affected by the DVT (Bouman and Cate-Hoek 2014, Prandoni et al. 1997). The use of elastic compression stockings (ECS) in patients with PTS has been derived from their perceived usefulness in established primary venous insuffiency (Bouman and Cate-Hoek 2014). Description of the condition Although there is no uniformly accepted definition of PTS (Ginsberg et al. 2001), it is generally described as a condition with symptoms ranging from swelling and edema of the lower extremity to outright ulcerations of the leg. Other symptoms include itching, ectatic veins, pain and paresthesias (Ginsberg et al. 2001, Kahn et al. 2013, Alatri et al. 2012, Bouman and Cate-Hoek 2014). Several scores have been developed to assess the severity of the condition, including the Ginsberg (Ginsberg et al. 2001) and Villalta (Prandoni et al. 1997) scales. Description of the intervention Compression stockings may be individually tailored, or off-the-rack (Kahn et al. 2013). They may be knee- or thigh high, and generally exert a pressure about mmhg (Alatri et al. 2012). How the intervention might work Compression stockings have been postulated to improve venous return through external compression, thus reducing edema and swelling in the extremity and improving the microcirculation (Prandoni et al. 2004). Why it is important to do this review Although compression stockings have been reported to be generally well tolerated (Prandoni et al. 2004), they are cumbersome for the patient, and treatment periods last for years, constituting a significant burden of treatment for the patients. It is important to establish whether the effect of this treatment is of a magnitude justifying such a long-time treatment. A search of the PROSPERO database (03 July 2014) did not identify any review covering this topic currently in progress.

2 Objectives To assess the benefits and harms of using elastic compression stockings (ECS) for the treatment of post-thrombotic syndrome (PTS). Methods Criteria for considering studies for this review Types of studies We will include randomized controlled trials (RCTs), and will also allow studies with a quasirandomized approach (i.e. based on birth date, order of enrolment into study etc.) in the review. Only clinical studies with humans subjects will be included, animal and in vitro studies will consequently be excluded. We will exclude observational studies. Types of participants We will include studies on patients having experienced a symptomatic deep vein thrombosis which has also been objectively diagnosed, either through ultrasonography, phlebography or another suitable radiographic modality. We define the patient population with established post-thrombotic syndrome as those patients having received delayed treatment (> 3 months after the DVT) and having symptoms of post-thrombotic syndrome at the time of treatment initiation. We perform a separate review for the use of ECS as secondary profylaxis against PTS, in which we include patients having received ECS within 3 months from the DVT occured, or patients without PTS symptoms having received ECS treament later than 3 months. We have made a pragmatic decision about these two separate populations as treatment start after index DVT events in RCTs identified in previous reviews varied significantly, between immediately and up to one year after the event (Musani et al. 2010). Types of interventions We will include studies using graduated compression stockings, both knee- and thigh high. Types of outcome measures Primary outcomes We will include patient-important outcomes, including: Symptom burden measured with a relevant validated clinical scale (Villalta, Ginsberg or other) Clinically important adverse events attributable to stocking use, including itching and rashes. We will not evaluate surrogate outcomes such as radiographically demonstrated vein impatency. Secondary outcomes We will evaluate benefits and harms of the intervention for the following secondary outcomes: Recurrent venous thrombosis (including DVT and PE) Death

3 Search methods for identification of studies Electronic searches We will search PubMed, Ovid MEDLINE and Ovid EMBASE (including EMBASE Classic) and Cochrane CENTRAL for relevant primary studies. Due to the more liberal indexing policies of EMBASE and hence larger output of EMBASE searches, we will exclude MEDLINE indexed journals in the search returns from EMBASE as we will assume these have been covered by the PubMed and Ovid MEDLINE searches. We will also search the Cochrane Database of Systematic Reviews, as well as CRD/York databases including DARE, NHS EED and HTA databases for previous reviews on the topic and examine the bibliographies of previous reviews in order to identify further references to primary studies. We will perform searches using relevant population and intervention freetext synonyms and relevant controlled vocabulary applicable to the database in question. We will not restrict searches by date or language, nor by outcome. We will not apply any filter. The full search strategies for each database are provided in the appendix. The search strategies have been developed by the the author (CFB) and peer-reviewed by trained medical librarians. For feasibility reasons, liteature search and screening for the population of this review (i.e. a PTS treatment setting) and a secondary prophylaxis setting after DVT for a separate review will be done simultaneously, as we expect large overlap in the search outputs. This is reflected in the search strategy. If anything, the concurrent search for the two populations is expected to increase the sensitivity of the search. Searching other resources We will hand-search bibliographies of included studies for other relevant studies not retrieved through the electronic search. Systematic reviews identified in the electronic search and deemed relevant to this topic by the screeners will first be checked against the Epistemonikos database to identify the primary studies used for the review (Epistemonikos 2014). If the review is not registered in Epistemonikos, the bibliography will be handsearched. We will also search clinicaltrials.gov for relevant studies currently in progress. Data collection and analysis Selection of studies Search outputs will be pooled and deduplicated using EndNote X7 (Thomson Reuters 2014). In the first round of screening, obviously irrelevant records will be excluded after independent duplicate examination of title and abstract. We will examine full texts of citations judged as potentially eligible by at least one reviewer. In the second round of screening, we will include RCTs and controlled clinical trials (CCTs) using a quasi-randomized approached as described above for the review. Screening will be performed independently by two reviewers (CFB and AK) using the web-based screening tool Covidence (Covidence 2014). We will seek to resolve disagreement by discussion. In case of unresolved disagreement, whether to include the study will be arbitrated by a third reviewer (POV). We will also screen the outputs from the Cochrane Database of Systematic Reviews and the CRD/York databases, although these are not likely to contain primary studies eligible for this review, but may potentially inform the retrieval of primary studies not identified by the initial electronic search through previously conducted reviews. These will also be screened in duplicate for relevancy to the review question, and the bibliographies of secondary literature deemed relevant will be examined as described above. As many of the hits from these databases are likely to return duplicate hits in PubMed, Ovid MEDLINE and Ovid EMBASE, we will pool returns from all databases to reduce the screening burden.

4 Data extraction and management Two reviewers (CFB and AK) will extract data independently using standardized data extraction forms in Covidence. In case of unresolved disagreement on the data extraction, a third reviewer (POV) will be consulted to reach an agreement. We will analyze data using RevMan 5.3 for metaanalyses (Cochrane 2014) and the SPSS statistical package for additional statistical analyses if needed (IBM 2013). If the Covidence data extraction form may not be fully adapted to extract all data needed, some data may be recorded using separate data extraction forms in Excel (Microsoft 2013). The field descriptions for the extraction form is provided in the appendix. Data for outcomes and subgroup-analyses from the primary studies will be registered in an appropriate tabular format for the intervention and non-intervention groups. We will contact authors for needed but unreported data. Assessment of risk of bias in included studies Risk of bias in the included studies will be assessed using the Cochrane collaboration's tool for assessing risk of bias. The risk of bias will be registered using the tool as provided in the Covidence web-based software. Measures of treatment effect Treatment effect will be analysed using the standard mean difference of the relevant PTS symptom evaluation scale as the unit of measurement, and as relative risks in the case of dichotomous outcomes. Unit of analysis issues Analyses will be performed using single primary studies as the unit of analysis. Dealing with missing data We will conduct a complete case analysis in the main meta-analysis. For assessing the impact of missing data across studies, we will conduct sensitivity analyses making progressively more stringent assumptions regarding loss to follow-up in intervention and control groups. The extent to which point estimates and confidence intervals (CIs) differ in these sensitivity analyses will determine whether we rate down for risk of bias. Assessment of heterogeneity We will assess heterogeneity through standard statistical methods, calculating a p value for χ 2 and an I 2 statistic. For the I 2, we will consider the following: 0 40% may be unimportant heterogeneity, 30 60% moderate, 50 90% substantial and % considerable heterogeneity. Assessment of reporting biases We will compute an inverted funnel plot and evaluate this visually to assess whether a publication bias is likely to be present in the material examined. Data synthesis For categorical data, we will calculate relative risks separately for each trial for the incidence of outcomes by treatment arm. We will then pool the results of the different trials using a random-effects model. For continuous data, we will calculate the standard mean difference separately for each trial. We will then pool the results of the different trials using a random-effects model. Subgroup analysis and investigation of heterogeneity Where data are available, we will perform subgroup analyses for proximal and distal localization of the DVT, respectively. We define a proximal DVT as a DVT in the popliteal vein or more proximal, as opposed to a distal DVT in the calf veins.

5 The lack of adequate blinding in studies where compression stockings have been used as the intervention (patients receiving no treatment rather than a placebo comparator) is a source of potentially substantial bias in the results, as lack of allocation concealment has been shown to inflate the magnitude of the intervention effect (Schulz 1995). If heterogeneity between blinded and non-blinded studies is detected, we will therefore perform subgroup analyses for the studies using placebo and no treatment comparators separately, calculating a ratio of odds ratios (ROR) between the groups. If a sufficient amount of studies may be included in the metaanalysis (i.e. 10 or more), we will consider performing a meta-regression and estimate whether there is significant difference in the effect estimates of the blinded and non-blinded studies, also assessing the amount of heterogeneity possibly explained by the lack or presence of allocation concealment. If appropriate considering the heterogeneity between blinded and non-blinded studies, we will perform a metaanalysis to calculate a pooled estimate of the treatment effects for the prespecified outcomes. Sensitivity analysis As described above, we will perform sensitivity analyses to assess the potential effect of missing data. We will also perform sensitivity analyses excluding studies at high risk of bias. Acknowledgements We would like to thank Marte Ødegaard at the University Library of Oslo for peer-reviewing the search strategy. References Alatri et al Alatri A, Calanca L, Tomson D, Mazzolai L.. [Prevention of post-thrombotic syndrome] [Prevention du syndrome post-thrombotique.]. Revue medicale suisse 2012/03/08;8(327): Bouman and Cate-Hoek 2014 Bouman, A. Cate-Hoek, A. T.. Timing and duration of compression therapy after deep vein thrombosis.. Phlebology 2014/05/21;29(1 suppl): Brandjes et al Brandjes, D. P.Buller, H. R.Heijboer, H.Huisman, M. V.de Rijk, M.Jagt, H.ten Cate, J. W.. Randomised trial of effect of compression stockings in patients with symptomatic proximalvein thrombosis. Lancet 1997/03/15;349(9054): Cochrane 2014 Review Manager (RevMan) [Computer program]. The Nordic Cochrane Centre. Version Version Copenhagen: The Cochrane Collaboration, Computer program. Covidence 2014 Covidence [Computer program]. Covidence. Melbourne, Epistemonikos 2014 Epistemonikos [Computer program]. Epistemonikos. Santiago, Chile: Epistemonikos (NGO), Ginsberg et al. 2001

6 Ginsberg JS, Hirsh J, Julian J, van der Laande Vries M, Magier D, MacKinnon B, Gent M.. Prevention and treatment of postphlebitic syndrome: results of a 3-part study. Arch Intern Med 2001/09/26;161(17): IBM 2013 IBM SPSS Statistics for Windows [Computer program]. IBM Corp.. Armonk, NY: IBM Corp., Kahn et al Kahn, S. R.Shapiro, S.Wells, P. S.Rodger, M. A.Kovacs, M. J.Anderson, D. R.Tagalakis, V. et al.. Compression stockings to prevent post-thrombotic syndrome: a randomised placebocontrolled trial. Lancet 2013/12/10;383(9920): Microsoft 2013 Microsoft Excel [Computer program]. Microsoft Corporation.. Redmond, Washington: Microsoft Corporation., Musani et al Musani, M. H.Matta, F.Yaekoub, A. Y.Liang, J.Hull, R. D.Stein, P. D.. Venous compression for prevention of postthrombotic syndrome: a meta-analysis. Am J Med 2010/07/31;123(8): Prandoni et al Prandoni, P.Villalta, S.Bagatella, P.Rossi, L.Marchiori, A.Piccioli, A.Bernardi, E.Girolami, B.Simioni, P.Girolami, A.. The clinical course of deep-vein thrombosis. Prospective long-term follow-up of 528 symptomatic patients. Haematologica 1997/07/01;82(4): Prandoni et al Prandoni, P.Lensing, A. W.Prins, M. H.Frulla, M.Marchiori, A.Bernardi, E.Tormene, D.Mosena, L.Pagnan, A.Girolami, A.. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med 2004/08/18;141(4): Schulz 1995 Schulz, K. F.Chalmers, I.Hayes, R. J.Altman, D. G.. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials.. JAMA 1995/02/01;273(5): Thomson Reuters 2014 EndNote X7 [Computer program]. Thomson Reuters. New York: Thomson Reuters, Computer program. Sources of support Internal sources Sykehuset Innlandet Hospital Trust, Norway The funds for this review were provided by Sykehuset Innlandet Hospital Trust as part of PhD and post-doc grants for the authors, respectively. External sources No sources of support provided

7 Appendices 1 PubMed search strategy Line number Search string 1 veno* thrombo* 2 DVT 3 deep vein thrombos* 4 VTE 5 thromboemboli* 6 tromboemboli* 7 postthrombo* syndrom* 8 post thrombo* syndrom* 9 posttrombo* syndrom* 10 post trombo* syndrom* 11 postphlebiti* syndrom* 12 post phlebiti* syndrom* 13 venous thrombosis[mh] 14 venous thromboembolism[mh] 15 postthrombotic syndrome[mh] 16 compression stocking* 17 compression therap* 18 ECS 19 elastic stocking* 20 compression garment* 21 stockings, compression[mh] 22 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 23 #16 OR #17 OR #18 OR #19 OR #20 OR #21 24 #22 AND #23 2 Ovid MEDLINE search strategy Line number Search string 1 veno* thrombo*.mp. 2 DVT.mp. 3 deep vein thrombos*.mp. 4 VTE.mp. 5 thromboemboli*.mp. 6 tromboemboli*.mp. 7 postthrombo* syndrom*.mp. 8 post-thrombo* syndrom*.mp. 9 posttrombo* syndrom*.mp. 10 post-trombo* syndrom*.mp.

8 11 postphlebiti* syndrom*.mp. 12 post-phlebiti* syndrom*.mp. 13 exp venous thrombosis/ 14 exp venous thromboembolism/ 15 exp postthrombotic syndrome/ 16 compression stocking*.mp. 17 compression therap*.mp. 18 ECS.mp. 19 elastic stocking*.mp. 20 compression garment*.mp. 21 exp stockings, compression/ 22 or/ or/ and/ Ovid EMBASE search strategy Line number Search string 1 veno* thrombo*.mp. 2 DVT.mp. 3 deep vein thrombos*.mp. 4 VTE.mp. 5 thromboemboli*.mp. 6 tromboemboli*.mp. 7 postthrombo* syndrom*.mp. 8 post-thrombo* syndrom*.mp. 9 posttrombo* syndrom*.mp. 10 post-trombo* syndrom*.mp. 11 postphlebiti* syndrom*.mp. 12 post-phlebiti* syndrom*.mp. 13 exp postthrombosis syndrome/ 14 exp vein thrombosis/ 15 compression stocking*.mp. 16 compression therap*.mp. 17 ECS.mp. 18 elastic stocking*.mp. 19 compression garment*.mp. 20 exp compression stocking/ 21 exp compression therapy/ 22 or/ or/ and/ limit 24 to exclude medline journals

9 4 Cochrane Library search strategy Line number Search string 1 veno* thrombo* 2 DVT 3 deep vein thrombos* 4 VTE 5 thromboemboli* 6 tromboemboli* 7 postthrombo* syndrom* 8 post-thrombo* syndrom* 9 posttrombo* syndrom* 10 post-trombo* syndrom* 11 postphlebiti* syndrom* 12 post-phlebiti* syndrom* 13 [mh "venous thrombosis"] 14 [mh "venous thromboembolism"] 15 [mh "postthrombotic syndrome"] 16 compression stocking* 17 compression therap* 18 ECS 19 elastic stocking* 20 compression garment* 21 [mh "stockings, compression"] 22 {OR #1-#15} 23 {OR #16-#21} 24 {AND #22-#23} 5 CRD/York databases search strategy Line number Search string 1 veno* thrombo* 2 DVT 3 deep vein thrombos* 4 VTE 5 thromboemboli* 6 tromboemboli* 7 postthrombo* syndrom* 8 post-thrombo* syndrom* 9 posttrombo* syndrom* 10 post-trombo* syndrom* 11 postphlebiti* syndrom*

10 12 post-phlebiti* syndrom* 13 MeSH DESCRIPTOR venous thrombosis EXPLODE ALL TREES 14 MeSH DESCRIPTOR venous thromboembolism EXPLODE ALL TREES 15 MeSH DESCRIPTOR postthrombotic syndrome EXPLODE ALL TREES 16 compression stocking* 17 compression therap* 18 ECS 19 elastic stocking* 20 compression garment* 21 MeSH DESCRIPTOR stockings, compression EXPLODE ALL TREES 22 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 23 #16 OR #17 OR #18 OR #19 OR #20 OR #21 24 #22 AND #23 6 Data extraction form Data extraction form Publication name (i.e. reference): Author completing this form: Date of completion of form: Notes: Details of study Aim of intervention: Aim of study: Study design: Method of recruiment of participants: Inclusion/exclusion criteria: Informed consent obtained? Ethical approval Funding (source, amount) Statistical methods applied Appropriateness of statistical methods YES/NO/UNCLEAR YES/NO/UNCLEAR Risk of bias: Please register in Covidence document Participants Description Geographical location Setting Number of eligible participants excluded refusing to take part

11 Mean age (+ standard deviation) Age range Gender Ethnicity Stage of PTS at inclusion randomised to intervention randomised to control excluded post randomization withdrawn lost to follow-up died included in analysis included for each outcome Treatment Details of intervention Details of control Details of co-interventions in all groups Delivery of intervention (timing, frequency, duration) Details of providers of intervention Was the intervention delivered as intended? Outcomes Primary outcomes (as stated by authors) Secondary outcomes (as stated by authors) Validity of outcome measures Methods of follow-up Timing of outcome assessment Adverse events Notes Contact with author? YES/NO Power calculation? YES/NO Translated from non-english, non-norwegian language? YES/NO Duplicate publication? YES/NO Results Please register in data section of Covidence file