TITLE

Protocol for a scoping review of outcomes in clinical studies of interventions for venous

thromboembolism in adults

AUTHORS

Tobias Tritschler1,2, Nicole Langlois1, Brian Hutton1, Beverley J. Shea1, Risa Shorr1, Sara

Ng1, Suzanne Dubois3, Carol West3, Alfonso Iorio4,5, Peter Tugwell1, Grégoire Le Gal1

AFFILIATIONS

1. Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa,

Ottawa, Ontario, Canada

2. Department of General Internal Medicine, Inselspital, Bern University Hospital,

University of Bern, Bern, Switzerland

3. Canadian Venous Thromboembolism Clinical Trials and Outcomes Research

(CanVECTOR) Network; Patient Partner Platform

4. Department of Health Research Methods, Evidence, and Impact, McMaster

University, Hamilton, Ontario, Canada

5. Department of Medicine, McMaster University, Hamilton, Ontario, Canada

6. Division of Hematology and Hematological Malignancies, Departments of Medicine

and Community Health Sciences, University of Calgary, Calgary, Canada

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CORRESPONDING AUTHOR

Grégoire Le Gal, The Ottawa Hospital, General Campus, Box 201A, 501 Smyth Road,

Ottawa, Ontario K1H 8L6, Canada; E-mail address: glegal@ohri.ca

WORD COUNT

1985

KEY WORDS

Core outcome set, Deep vein thrombosis, Pulmonary embolism, Outcome research,

Venous thromboembolism

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ABSTRACT

Introduction: Venous thromboembolism (VTE) is a common, potentially fatal yet

treatable disease. Several advances in treatment of VTE have been made over the past

decades, but definition and reporting of outcomes across those studies are inconsistent.

Development of an international core outcome set for clinical studies of interventions for

VTE addresses this lack of standardization. The first step in the development of a core

outcome set is to conduct a scoping review which aims to generate an inclusive list of

unique outcomes that have been reported in previous studies.

Methods and analysis: MEDLINE, Embase, and the Cochrane Central Register of

Controlled Trials will be searched with no language restriction for prospective studies

reporting on interventions for treatment of VTE in adult non-pregnant patients. Records

will be sorted in reverse chronologic order. Study screening and data extraction will be

independently performed by 2 authors in blocks based upon date of publication, starting

with 2015-2020 and subsequent 1-year periods, until no new outcome measures are

identified from the set of included studies. After homogenizing spelling and combining

outcomes with the same meaning, a list of unique outcomes will be determined. Those

outcomes will be grouped into outcome domains. Qualitative analysis and descriptive

statistics will be used to report results.

Ethics and dissemination: Ethical approval is not required for this study. The results of

this scoping review will be presented at scientific conferences, published in a peer-

reviewed journal, and they will provide candidate outcome domains to be considered in

subsequent steps in the development of a core outcome set for clinical studies of

interventions for VTE.

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INTRODUCTION

Rationale

Venous thromboembolism (VTE) is a common condition manifested as deep vein

thrombosis (DVT) or pulmonary embolism (PE). If left untreated, the reported mortality of

PE has varied widely in historical and more recent studies,[1,2] but timely and

appropriate treatment with anticoagulant medications dramatically reduces fatal events

to less than 1%.[3] In addition to PE-related death, most VTE treatment studies

incorporate recurrent VTE or bleeding as primary or secondary outcomes. However, it

has been noted that the list, definition and reporting of outcomes is inconsistent across

studies and discrepancies in how these outcomes are defined and measured have led to

important challenges in comparing and synthesizing the results of trials.[4] Lack of valid

and standardized definitions of domains and measures for certain outcomes has also

compromised the ability to demonstrate clinically meaningful effects. For example, how

severe a bleeding event should be to count as an outcome has been a matter of debate.

[5] The definition of PE-related death is variable between studies,[6] and within a single

study the outcome adjudicators demonstrated poor reproducibility (50% discordant

results) for unexplained sudden death adjudicated as PE-related.[7] Beneficial and

safety outcomes beyond mortality, recurrent VTE and bleeding, such as post-thrombotic

syndrome, quality of life, symptom resolution or psychological effects, are rarely

measured in VTE studies,[8,9] even though their impact on patients’ health and

economic burden of VTE may be relevant. Of note, no study to date has assessed which

outcomes are most important to patients and caregivers.

The development of a core outcome set (COS), defined as an agreed minimum set

of outcomes that should be measured and reported in all trials of a specific condition,

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addresses this lack of standardization. The Core Outcome Measures in Effectiveness

Trials (COMET) and Outcome Measures in Rheumatology (OMERACT) initiatives aim to

stimulate the development and application of COS, adopting best practices and robust

methodology that are based on evidence.[10,11] The first step in the development of a

COS includes a scoping review of the literature to identify outcomes and domains that

have been used previously. The results of the scoping review will help to determine the

heterogeneity of reported outcomes and establish a list of unique outcomes. The results

of this scoping review, considered together with the findings of other planned qualitative

work involving multiple stakeholders (including patients, caregivers, clinicians,

researchers, clinical practice guideline developers, health technology assessors, payers,

policy makers, public research funding agencies, and drug developers), will inform

candidate outcomes and domains for the final consensus process to determine the COS

for clinical studies of interventions for VTE.

Objectives

Primary objective

The primary objective of the scoping review is to generate an inclusive list of unique

outcome domains that have been reported in previous VTE treatment studies.

Secondary objectives

The secondary objectives are to assess the number of unique outcome domains and

measures reported (i.e., outcome reporting heterogeneity),[12] to assess the number of

unique outcomes reported per study, to assess the presence of different wording for the

same outcomes, to assess different timepoints at which unique outcomes are measured,

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to assess the number of patient-reported unique outcomes, and to capture outcome

definitions.

METHODS AND ANALYSIS

This protocol was developed following guidance in the COMET and Outcome Measures

in Rheumatology (OMERACT) handbooks and reporting adheres to the Preferred

Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P)

Statement (supplementary appendix 1).[10,11,13] The VTE-COS project is registered

with the COMET database (http://www.comet-initiative.org). Reporting of the scoping

review will adhere to the PRISMA statement items on scoping reviews.[14]

Eligibility criteria

Participants

We will seek studies that enrolled adults diagnosed with VTE, either DVT of the legs,

PE, or both. We will exclude VTE studies which included only pregnant women,

comprising the ante-partum, peri-partum and post-partum periods, because an ongoing

systematic review already assesses reported outcomes in this specific population

(PROSPERO registration number CRD42019111479).

Interventions

We are interested in 9 categories of interventions for treatment of VTE: 1.

anticoagulation; 2. aspirin and other nonsteroidal anti-inflammatory drugs; 3. statins; 4.

thrombolysis; 5. surgery; 6. venous filters; 7. pharmacomechanical catheter-directed

thrombolysis; 8. venous angioplasty and stenting; and 9. compression stockings.

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Studies involving the evaluation of other therapies will be excluded. Because of the wide

range of treatment options for VTE, some outcome domains may only be relevant to

certain therapies or subpopulation of patients. While these may not be mandatory

domains in the final core outcome set, they may represent important but optional

domains or research agenda domains according to the OMERACT onion schema [11].

As such, the categorization of interventions will not only be collected to characterize

included studies but also considered in study selection and data extraction (see “data

management and selection process”).

Outcome

This review will capture all outcomes reported in the included studies.

Study design

Randomized controlled trials and prospective cohort studies will be eligible.

Search strategy

An experienced information specialist developed the strategy for structured database

searches in consultation with the review team. The search strategy was peer reviewed

according to the Peer Review of Electronic Search Strategies (PRESS) guideline

statement by a second independent information specialist before being finalized.[15]

Databases to be searched will include MEDLINE, Embase, and the Cochrane Central

Register of Controlled Trials. No language restrictions will be in place. The search

strategy for MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials

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for the first block of studies to be screened (i.e., 2014-2020; see “data management and

selection process”) is provided in the supplementary appendix 2.

Data management and selection process

Screening of studies at both the title/abstract level (Level 1 screening) and the full text

level (Level 2 screening) will be implemented in Covidence, an online software

management program for the performance of systematic reviews.[16] All documents will

be reviewed independently by two team members. Disagreement will be resolved by

discussion or by involving a third reviewer, if needed. A flow diagram summarizing the

process of study selection will be prepared.

To maximize efficiency of the study selection process, titles/abstracts for Level 1

screening will be sorted in reverse chronologic order and will be screened in blocks

based upon date of publication. To begin, studies published between 2015-2020 will be

screened at both abstract and full text level to establish a full set of included studies for

this time period. Data extraction from these studies (methods described below) will be

performed in full to establish a complete ‘map’ of all the outcomes measured in the set

of included studies. Subsequently, in one-year intervals (i.e. 2014, 2013, 2012, etc.), the

same approach will be taken; selection of additional studies for inclusion will be halted

when, for a one-year period, no new outcome measures are identified from the set of

included studies (commonly referred to as ‘saturation’ in terms of outcome measures).

This approach is recommended by COMET and OMERACT guidance and results in a

robust source of information for the review while offering efficiencies in both study

selection and data extraction.[10,11] Because studies assessing different categories of

interventions may be variably represented over time, saturation will be assessed for

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each of the 9 above-defined intervention categories. If a certain category is not

represented by at least 1 study within one of the assessment periods (i.e., 2015-2020

and subsequent 1-year periods), selection of additional studies will not be halted for this

particular category.

Data extraction

For all included studies identified using the above approach, extracted data from each

report will include the characteristics of the study (design, year, country, interventions,

follow-up duration), as well as the set of reported outcomes, outcome definitions,

outcome measurement tools, timing of measurement and metrics. Outcome descriptions

will be extracted verbatim. All data of interest will be extracted from the source

publications by 2 authors independently.

Outcomes and prioritization

The primary outcome of the study is a list of unique outcomes reported in the included

studies. A unique outcome will be defined as one that has original meaning and context.

[12] Outcomes differing only in timing of the outcome assessment (e.g., 10-day versus

30-day all-cause mortality) will not be considered unique. We will extract outcomes

verbatim and also record each outcome’s definition, timing of assessment, measurement

and metrics. The selection process of unique outcomes will follow the proposal of Young

et al.[12] First, duplicate verbatim outcomes will be removed after homogenizing spelling

(e.g., bleeding and bleed, rates and rate, etc.). Second, outcomes meaning the same

will be re-written by 2 reviewers independently to develop non-verbatim outcomes. The

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re-writing process will be documented. Finally, outcomes remaining after removal of

duplicate non-verbatim outcomes will define the list of unique outcomes.

Risk of bias (quality) assessment

Given that the purpose of this review is to develop an inclusive set of outcome domains

in order to inform subsequent steps in the VTE-COS development, no risk of bias

assessment will be performed. This is consistent with recommendations in the PRISMA

extension for scoping reviews.[14]

Data synthesis

We will use descriptive statistics to report the number of verbatim outcomes reported

overall and in each individual study and the number of terms used to describe a single

unique outcome. Furthermore, we will report the number of unique outcomes overall and

per study, definitions of unique outcomes including timepoints of assessment, as well as

the number of physician-reported and patient-reported unique outcomes.

Similar unique outcomes will be grouped into domains. A domain is defined as a

component or concept of “an aspect of health or health condition that needs to be

measured to appropriately assess the effects of a health intervention”.[11] Once several

domains have been identified, outcomes within domains will be checked for internal

homogeneity (i.e., coherence of outcomes within domain) and external heterogeneity

(i.e., distinction to outcomes in other domains).[17] As per OMERACT filter 2.1, the final

list of domains will be categorized into 4 core areas including

manifestations/abnormalities, life impact, death/lifespan, and societal/resource use.[18]

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We will use descriptive statistics to report the number of domains and core areas

covered in each individual study and vice versa. In subgroup analyses, we will assess

differences related to above-mentioned descriptive statistics between randomized

controlled trials and prospective cohort studies, and between different locations of initial

VTE (i.e., studies for which patients were eligible if they had DVT vs. PE vs. VTE).

Confidence in cumulative evidence

Because we aim to capture and describe what outcomes have been reported in previous

VTE studies, determination of the strength of evidence is not applicable.

Patient and public involvement

Patient partners of the Canadian Venous Thromboembolism Clinical Trials and

Outcomes Research (CanVECTOR) Network contributed to the concept and protocol of

this scoping review and will be involved in the dissemination of the results.

ETHICS AND DISSEMINATION

Ethical approval is not required for this study because this is a scoping review of

published studies.

In this scoping review, we aim to generate a list of unique outcome domains

reported in previous studies of VTE treatment. This list will serve to define core domains

to be considered in the development of a COS for VTE treatment studies. Subsequent

steps of the COS development project include 1) individual interviews and focus groups

of different stakeholders to identify additional candidate domains which are important for

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patients and other stakeholders and to increase understanding of stakeholder-relevant

outcomes; 2) a Delphi survey to add additional previously not identified outcomes and to

prioritize outcomes; 3) a consensus meeting among the study researchers and key

stakeholders to define the final COS; and 4) the dissemination of the final COS.

The findings of this scoping review will be disseminated through a peer-reviewed

journal publication and presentations at scientific conferences. As part of the VTE-COS

project, the study is endorsed by the International Society on Thrombosis and

Haemostasis (ISTH), the CanVECTOR network and the International Network of

VENous Thromboembolism Clinical Research Networks (INVENT). In addition to

publication and presentation of the study findings, we will use their platforms to foster

dissemination of results to researchers, knowledge users and patients in form of

audience-specific summary reports.

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FUNDING

The VTE-COS project is funded by the Canadian Institutes of Health Research (PJT-

165897) and is supported by the CanVECTOR Network; the Network receives grant

funding from the Canadian Institutes of Health Research (CDT-142654). The funder

played no role in developing the protocol.

ACKNOWLEDGEMENT

Tobias Tritschler holds an Early Postdoc. Mobility Award from the Swiss National

Science Foundation (SNSF P2ZHP3_177999) and a Fellowship Award from the

CanVECTOR Network. Grégoire Le Gal holds an Early Researcher Award from the

Province of Ontario, a mid-career clinician scientist award from the Heart and Stroke

Foundation of Ontario, and the Chair on the Diagnosis of Venous Thromboembolism,

Department of Medicine, University of Ottawa.

COMPETING INTERESTS

The authors state that they have no competing interests.

AUTHOR CONTRIBUTIONS

All authors contributed to concept and design of the study. TT, NL, BH and GLG wrote

the manuscript. All authors reviewed and revised the manuscript. All authors approved

the final version of the manuscript.

Page 13 of 21

REFERENCES

1. Nieto JA, Vicente JA, Prieto LM, et al. Thirty-day outcomes in patients with acute

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2018/10/03]

2. Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism.

A controlled trial. Lancet 1960;1(7138):1309-12. doi: 10.1016/s0140-

6736(60)92299-6

3. Carrier M, Le Gal G, Wells PS, et al. Systematic review: case-fatality rates of

recurrent venous thromboembolism and major bleeding events among patients

treated for venous thromboembolism. Ann Intern Med 2010;152(9):578-89. doi:

10.7326/0003-4819-152-9-201005040-00008 [published Online First: 2010/05/05]

4. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018

guidelines for management of venous thromboembolism: optimal management of

anticoagulation therapy. Blood Adv 2018;2(22):3257-91. doi:

10.1182/bloodadvances.2018024893 [published Online First: 2018/11/30]

5. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific

Standardization Committee of the International Society on Thrombosis

Haemostasis. Definition of major bleeding in clinical investigations of

antihemostatic medicinal products in non-surgical patients. J Thromb Haemost

2005;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x [published Online First:

2005/04/22]

6. Kraaijpoel N, Tritschler T, Guillo E, et al. Definitions, adjudication, and reporting of

pulmonary embolism-related death in clinical studies: A systematic review. J

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Thromb Haemost 2019;17(10):1590-607. doi: 10.1111/jth.14570 [published

Online First: 2019/07/14]

7. Girard P, Penaloza A, Parent F, et al. Reproducibility of clinical events adjudications

in a trial of venous thromboembolism prevention. J Thromb Haemost

2017;15(4):662-69. doi: 10.1111/jth.13626 [published Online First: 2017/01/17]

8. Klok FA, Barco S, Siegerink B. Measuring functional limitations after venous

thromboembolism: A call to action. Thromb Res 2019;178:59-62. doi:

10.1016/j.thromres.2019.04.003 [published Online First: 2019/04/14]

9. Kahn SR, Houweling AH, Granton J, et al. Long-term outcomes after pulmonary

embolism: current knowledge and future research. Blood Coagul Fibrinolysis

2014;25(5):407-15. doi: 10.1097/MBC.0000000000000070 [published Online

First: 2014/01/29]

10. Williamson PR, Altman DG, Bagley H, et al. The COMET Handbook: version 1.0.

Trials 2017;18(Suppl 3):280. doi: 10.1186/s13063-017-1978-4 [published Online

First: 2017/07/07]

11. OMERACT Initiative. The OMERACT Handbook. 2018. Available at

https://omeracthandbook.org Accessed 21 April, 2020.

12. Young AE, Brookes ST, Avery KNL, et al. A systematic review of core outcome set

development studies demonstrates difficulties in defining unique outcomes. J Clin

Epidemiol 2019;115:14-24. doi: 10.1016/j.jclinepi.2019.06.016 [published Online

First: 2019/07/06]

13. Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic

review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev

2015;4:1. doi: 10.1186/2046-4053-4-1 [published Online First: 2015/01/03]

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14. Tricco AC, Lillie E, Zarin W, et al. PRISMA Extension for Scoping Reviews

(PRISMA-ScR): Checklist and Explanation. Ann Intern Med 2018;169(7):467-73.

doi: 10.7326/M18-0850 [published Online First: 2018/09/05]

15. McGowan J, Sampson M, Salzwedel DM, et al. PRESS Peer Review of Electronic

Search Strategies: 2015 Guideline Statement. J Clin Epidemiol 2016;75:40-6. doi:

10.1016/j.jclinepi.2016.01.021 [published Online First: 2016/03/24]

16. Covidence systematic review software, Veritas Health Innovation, Melbourne,

Australia. Available at www.covidence.org.

17. Patton MQ. Qualitative Research and Evaluation Methods. 4 ed: SAGE 2014.

18. Boers M, Beaton DE, Shea BJ, et al. OMERACT Filter 2.1: Elaboration of the

Conceptual Framework for Outcome Measurement in Health Intervention Studies.

J Rheumatol 2019;46(8):1021-27. doi: 10.3899/jrheum.181096 [published Online

First: 2019/02/17]

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SUPPLEMENTARY MATERIAL

Supplementary appendix 1. PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist.

Section and topic

Item No

Checklist item Page

ADMINISTRATIVE INFORMATIONTitle:

 Identification

1a Identify the report as a protocol of a systematic review 1

 Update 1b If the protocol is for an update of a previous systematic review, identify as such

N/A

Registration 2 If registered, provide the name of the registry (such as PROSPERO) and registration number

6

Authors: Contact 3a Provide name, institutional affiliation, e-mail address of all protocol authors;

provide physical mailing address of corresponding author2

 Contributions

3b Describe contributions of protocol authors and identify the guarantor of the review

13

Amendments 4 If the protocol represents an amendment of a previously completed or published protocol, identify as such and list changes; otherwise, state plan for documenting important protocol amendments

N/A

Support: Sources 5a Indicate sources of financial or other support for the review 13 Sponsor 5b Provide name for the review funder and/or sponsor 13 Role of sponsor or funder

5c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the protocol

13

INTRODUCTIONRationale 6 Describe the rationale for the review in the context of what is already

known4-5

Objectives 7 Provide an explicit statement of the question(s) the review will address with reference to participants, interventions, comparators, and outcomes (PICO)

5

METHODSEligibility criteria 8 Specify the study characteristics (such as PICO, study design, setting, time

frame) and report characteristics (such as years considered, language, publication status) to be used as criteria for eligibility for the review

6-8

Information sources

9 Describe all intended information sources (such as electronic databases, contact with study authors, trial registers or other grey literature sources) with planned dates of coverage

7

Search strategy 10 Present draft of search strategy to be used for at least one electronic database, including planned limits, such that it could be repeated

19-22

Study records:Data management

11a Describe the mechanism(s) that will be used to manage records and data throughout the review

7-8

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Selection process

11b State the process that will be used for selecting studies (such as two independent reviewers) through each phase of the review (that is, screening, eligibility and inclusion in meta-analysis)

7-8

Data collection process

11c Describe planned method of extracting data from reports (such as piloting forms, done independently, in duplicate), any processes for obtaining and confirming data from investigators

8-9

Data items 12 List and define all variables for which data will be sought (such as PICO items, funding sources), any pre-planned data assumptions and simplifications

9

Outcomes and prioritization

13 List and define all outcomes for which data will be sought, including prioritization of main and additional outcomes, with rationale

9

Risk of bias in individual studies

14 Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be done at the outcome or study level, or both; state how this information will be used in data synthesis

10

Data synthesis 15a Describe criteria under which study data will be quantitatively synthesised 915b If data are appropriate for quantitative synthesis, describe planned

summary measures, methods of handling data and methods of combining data from studies, including any planned exploration of consistency (such as I2, Kendall’s τ)

10

15c Describe any proposed additional analyses (such as sensitivity or subgroup analyses, meta-regression)

10-11

15d If quantitative synthesis is not appropriate, describe the type of summary planned

10-11

Meta-bias(es) 16 Specify any planned assessment of meta-bias(es) (such as publication bias across studies, selective reporting within studies)

N/A

Confidence in cumulative evidence

17 Describe how the strength of the body of evidence will be assessed (such as GRADE)

11

* It is strongly recommended that this checklist be read in conjunction with the PRISMA-P Explanation and Elaboration (cite when available) for important clarification on the items. Amendments to a review protocol should be tracked and dated. The copyright for PRISMA-P (including checklist) is held by the PRISMA-P Group and is distributed under a Creative Commons Attribution Licence 4.0.

From: Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart L, PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015 Jan 2;349(jan02 1):g7647.

Page 18 of 21

Supplementary appendix 2. Electronic search strategy.

Database: Embase Classic+Embase <1947 to current>, Ovid MEDLINE(R) ALL <1946 to current>, EBM Reviews - Cochrane Central Register of Controlled Trials <Current>Search Strategy:--------------------------------------------------------------------------------1 *thrombosis/dt, th, su or *thromboembolism/dt, th, su or *venous thromboembolism/dt, th, su or *venous thrombosis/dt, th, su2 *Pulmonary Embolism/dt, th, su3 ((pulmonary or lung) and embol*).ti.4 ((vein or venous) and thromb*).ti.5 (pe or dvt or vte).ti.6 (pulmonary embol* or lung embol*).kw.7 (venous thrombo* or vein thrombo*).kw.8 (pe or dvt or vte).kw.9 exp *Thrombophlebitis/dt, su, th [Drug Therapy, Surgery, Therapy]10 Thrombophlebitis.ti,kw.11 (superficial and thrombosis).ti.12 (superficial and thrombosis).kf.13 or/1-1214 Anticoagulants/ or exp Anticoagulants/tu15 exp Factor Xa Inhibitors/16 (rivaroxaban or apixaban or edoxaban or betrixaban or danaproid or darexaban).mp.17 Antithrombins/18 (dabigatran or ximelagatra).mp.19 exp Vitamin K/ai [Antagonists & Inhibitors]20 (Coumadin or warfarin or phenprocoumon or marcoumar or acenocoumaro).mp.21 exp Heparin, Low-Molecular-Weight/22 (dalteparin or fragmin or enoxaparin or clexane or lovenox or nadroparin or fraxiparin or fondaparinux or arixtra or bemiparin or semuloparin or sulodexide).mp.23 Heparin/24 (heparin or liquemin or liquaemin).mp.25 exp Anti-Inflammatory Agents, Non-Steroidal/26 aspirin.tw,kw.27 exp Hydroxymethylglutaryl-CoA Reductase Inhibitors/28 (Atorvastatin or fluvastatin or lovastatin or pravastatin or rosuvastatin or simvastatin or pitavastatin).mp.29 exp Thrombolytic Therapy/30 Mechanical Thrombolysis/31 fibrinolytic agents/ or streptokinase/ or tissue plasminogen activator/32 Urokinase-Type Plasminogen Activator/33 (streptokinase or urokinase or recombinant tissue plasminogen activator or rt-PA or alteplase).mp.34 exp Thrombectomy/35 (thrombectom* or Thrombolysis).tw,kw.36 Vena Cava Filters/37 vena cava filter*.tw,kw.38 (Catheter-directed adj2 (treatment or management or therapy)).tw.39 Ultrasound-assisted thrombolysis.tw,kw.40 stents/ or angioplasty/41 ((vein or venous) adj3 (stent* or angioplast*)).tw. or (stent* or angioplast*).ti.42 Stockings, Compression/43 Compression stocking*.tw,kw.44 or/14-4345 13 and 4446 randomized controlled trial.pt.47 controlled clinical trial.pt.48 random*.tw.49 placebo.ab.

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50 clinical trials as topic.sh.51 trial.ti. (824446)52 cohort studies/ or prospective studies/53 prospective*.tw.54 or/46-5355 45 and 5456 limit 55 to yr="2014 -Current"57 56 use medall58 45 use cctr59 limit 58 to yr="2014 -Current"60 *deep vein thrombosis/dm, dt, th, su61 *lung embolism/dm, dt, th, su62 *vein thrombosis/dm, dt, th, su63 *thrombosis/dm, dt, th, su64 *thromboembolism/dm, dt, th, su65 *venous thromboembolism/dm, dt, th, su66 *vein thrombosis/dm, dt, th, su67 ((pulmonary or lung) and embol*).ti.68 ((vein or venous) and thromb*).ti.69 (pe or dvt or vte).ti.70 *thrombophlebitis/dm, dt, su, th71 *superficial thrombophlebitis/dm, dt, su, th72 *leg thrombophlebitis/dm, dt, su, th73 thrombophlebitis.ti.74 (superficial and thrombosis).ti.75 or/60-7476 exp *anticoagulant agent/dt, th or anticoagulant agent/77 exp blood clotting factor 10a inhibitor/78 (rivaroxaban or apixaban or edoxaban or betrixaban or danaproid or darexaban).tw.79 antithrombin/80 (dabigatran or ximelagatra).mp.81 antivitamin K/82 (Coumadin or warfarin or phenprocoumon or marcoumar or acenocoumaro).mp.83 exp low molecular weight heparin/84 (dalteparin or fragmin or enoxaparin or clexane or lovenox or nadroparin or fraxiparin or fondaparinux or arixtra or bemiparin or semuloparin or sulodexide).tw.85 heparin/86 (heparin or liquemin or liquaemin).tw.87 exp nonsteroid antiinflammatory agent/88 aspirin.tw.89 exp hydroxymethylglutaryl coenzyme A reductase inhibitor/90 (Atorvastatin or fluvastatin or lovastatin or pravastatin or rosuvastatin or simvastatin or pitavastatin).tw.91 fibrinolytic therapy/92 exp mechanical thrombectomy/93 fibrinolytic agent/ or exp plasminogen activator/94 (streptokinase or urokinase or recombinant tissue plasminogen activator or rt-PA or alteplase).tw.95 (thrombectom* or Thrombolysis).tw.96 vena cava filter/97 vena cava filter*.tw.98 (Catheter-directed adj2 (treatment or management or therapy)).tw.99 blood clot lysis/100 vascular stent/ or venous stent/101 angioplasty/102 ((vein or venous) adj3 (stent* or angioplast*)).tw.103 (stent* or angioplast*).ti.104 compression stocking/

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105 Compression stocking*.tw.106 or/76-105107 75 and 106108 random*.tw. or placebo*.mp. or double-blind*.tw.109 prospective study/110 cohort analysis/ and prospective*.tw.111 (prospective* adj5 (stud* or analysis)).tw.112 or/108-111113 107 and 112114 limit 113 to yr="2014 -Current"115 114 use emczd116 57 or 59 or 115117 116 use medall Medline118 116 use emczd Embase119 116 use cctr Cochrane

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