Article Text

Quality evaluation of clinical practice guidelines for thromboprophylaxis in orthopaedic trauma based on AGREE II and AGREE-REX: a systematic review protocol
  1. Ling-Xiao He1,2,
  2. Jing-Ying Xie1,3,
  3. Juan Lv1,4,
  4. Huan Liu1,5,
  5. Deng-Bin Liao1,2,
  6. Guang-Lin Wang2,6,
  7. Ning Ning1,7,
  8. Zong-Ke Zhou6,7
  1. 1School of Nursing, West China Hospital, Sichuan University, Chengdu, Sichuan, China
  2. 2Trauma Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
  3. 3West China Hospital of Stomatology, Sichuan Universtiy, Chengdu, Sichuan, China
  4. 4Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
  5. 5Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
  6. 6West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
  7. 7Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
  1. Correspondence to Dr Zong-Ke Zhou; zhouzongke{at}


Introduction Orthopaedic trauma patients are at high risk of venous thromboembolism (VTE). As VTE prophylaxis has gradually raised public concerns, guidelines related to this topic have increased over time. However, the existing recommendations of thromboprophylaxis guidelines in orthopaedic trauma patients are still inconsistent, and the quality of the guidelines and recommendations for the topic still lacks comprehensive assessments. This review aims to critically appraise clinical practice guidelines for thromboprophylaxis in orthopaedic trauma patients.

Methods and analysis We will conduct a comprehensive literature search up to 31 October 2022 in databases (PubMed, EMBASE, CINAHL, Web of Science, the Cochrane Library, etc), academic websites and guideline repositories. The quality of the guidelines and recommendations will be assessed by five reviewers independently using the Appraisal of Guidelines Research and Evaluation II instrument (AGREE-II) and the AGREE - Recommendation EXcellence (AGREE-REX). We will summarise the characteristics of the guidelines and compare the differences between these recommendations.

Ethics and dissemination This study will follow the Declaration of Helsinki and has received approval from the Ethics Committee on Biomedical Research, West China Hospital, Sichuan University (ethics approval no. 2021-989). The results will be summarised as a paper, disseminated through peer-reviewed journals, and will help guide further research in the future.

Protocol registration number CRD42021273405.

  • protocols & guidelines
  • trauma management
  • orthopaedic & trauma surgery

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  • We will evaluate the quality of clinical practice guidelines and the applicability of the recommendations in guidelines related to venous thromboembolism prevention in orthopaedic trauma patients to guide evidence-based clinical practice.

  • We will conduct a comprehensive literature search and use the widely recognised Appraisal of Guidelines Research and Evaluation II (AGREE-II) and AGREE-Recommendation EXcellence tools for rigorous quality evaluation.

  • All the members will not participate in the quality appraisal until received systematic review training.

  • This study will be limited to guidelines written in Chinese and English, which could be a limiting factor.

  • This study might be included in guidelines that were developed earlier or not updated in time. Thus, more cautious interpretations of the study results should be needed.


Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is the third most common cause of cardiovascular-related death and results in a mass of disability-adjusted life-years lost in hospitalised patients.1 More than 500 000 VTE-related deaths occur in the USA1 and cost US$7–US$10 billion for healthcare annually.2 As an avoidable in-hospital complication, each case of VTE will take an excess of 5.4 hospitalisation days and increase the mortality rate by 6.6 times.3 About 6% of patients with DVT and 12% of patients with PE die within 1 month after diagnosis.4 Various factors can lead to the occurrence of VTE, such as major surgery, trauma, plaster fixation, tumours, etc.5 Orthopaedic trauma patients are at high risk of VTE due to multiple risk factors. The incidence of VTE in orthopaedic trauma patients can vary from 4.78% to 40.25%,6–9 depending on the location of the injury, VTE monitoring method, ethnicity, etc.

Thromboprophylaxis has been proven able to reduce the occurrence of VTE effectively.10 Both chemical and mechanical prophylaxis strategies have shown their effects in orthopaedic trauma patients. At present, the most widely used VTE prevention clinical practice guideline (CPG) in orthopaedic surgery is the ninth edition of the VTE prevention guideline presented by the American College of Chest Physicians (ACCP) in 2012.11 However, its recommendations for patients with orthopaedic trauma are insufficient, covering only patients with hip fractures, isolated lower leg injuries and knee arthroscopy. And no specific recommendations for the dose and frequency of chemoprophylaxis are mentioned in the above ACCP guideline. Recently, several updated CPGs for VTE prevention have been published,12–19 but many have been formed based on expert consensus.14 15 18 19 In addition, there are still many issues to be determined,20 such as the timing, duration and best practice protocol for VTE prevention in patients with different types of orthopaedic trauma. It is still necessary to explore further construction of a VTE prevention programme that fits the clinical situation of orthopaedic trauma patients based on guidelines.

Currently, the Appraisal of Guidelines for Research & Evaluation II instrument (AGREE-II)21 is widely accepted to evaluate the methodological quality of the guidelines. However, this tool does not assess the specific recommendations provided in the guidelines and cannot guarantee their applicability in clinical practice. The AGREE-Recommendation EXcellence (AGREE-REX) tool22 mainly evaluates the quality and applicability of the guideline recommendations, which is a powerful supplement to AGREE-II. We hope to use the AGREE-II and AGREE-REX tools to critically appraise the current CPGs for VTE prevention in orthopaedic trauma and understand both the methodological and recommendation quality of the current guidelines, which help guide the selection of reliable recommendations following the clinical situation.

Methods and analysis


We plan to systematically collect VTE prophylaxis CPGs in the field of orthopaedic trauma and use AGREE-II and AGREE-REX tools to conduct a rigorous quality appraisal to answer the following questions:

  1. What is the methodological quality of the VTE prophylaxis CPGs in orthopaedic trauma?

  2. What similarities and differences are the recommendations provided in the current CPGs for VTE prophylaxis in orthopaedic trauma?

  3. What is the strength and quality of the evidence provided in the current CPGs for VTE prophylaxis in orthopaedic trauma?

Protocol and registration

This report follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol statement (see online supplemental appendix 1) and has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD42021273405.

Patient and public involvement

Patients and/or the public will not be involved in the design, conduct, reporting or dissemination plans of this research.

Eligibility criteria

See details in table 1. We will only include openly published literature in the study and grey literature will be excluded.

Table 1

Inclusion and exclusion criteria

Selection of studies

Data sources

The following databases and websites from inception to 31 October 2022 will be searched:

  1. Electronic databases: PubMed, EMBASE, CINAHL, Web of Science, the Cochrane Library, SinoMed, CNKI and WanFang.

  2. Academic websites: WHO (, Centers for Disease Control and Prevention (CDC,, American Academy of Orthopedic Surgeons (AAOS,, American College of Chest Physicians (ACCP,, Registered Nurses Association of Ontario (RNAO,, Chinese Medical Association (CMA,

  3. Guideline repositories: Guidelines International Network, National Institute for Health and Care Excellence, New Zealand Guidelines Group, Scottish Intercollegiate Guidelines Network, CPG-Infobase, National Health & Medical Research Council, JBI database, Clinical Key, UpToDate.

  4. others: any additional guidelines identified from references of eligible guidelines.

Search strategies

Terms related to “orthopedic trauma”, “VTE”, “prevention” and “guideline” will be adopted for the search in each database. Detailed search strategies are listed in online supplemental appendix 2. An example of a database search strategy is shown in box 1.

Box 1

Sample research strategy for PubMed

#1 ((orthopedics[MeSH Terms]) OR (traumatology[MeSH Terms])) OR (wounds and injuries[MeSH Terms])

#2 (((((((fracture[Title/Abstract]) OR (limb trauma[Title/Abstract])) OR (extremity trauma[Title/Abstract])) OR (musculoskeletal injur*[Title/Abstract])) OR (musculoskeletal trauma[Title/Abstract])) OR (limb immobili*[Title/Abstract])) OR (skeletal fixation[Title/Abstract])) OR ("orthop*"[Title/Abstract] AND "trauma"[Title/Abstract])

#3 ((venous thromboembolism[MeSH Terms]) OR (venous thrombosis[MeSH Terms])) OR (pulmonary embolism[MeSH Terms])

#4 (((((((((((venous thromboembolism[Title/Abstract]) OR (venothromboembolism[Title/Abstract])) OR (venous thrombosis[Title/Abstract])) OR (vein thrombosis[Title/Abstract])) OR (DVT[Title/Abstract])) OR (VTE[Title/Abstract])) OR (pulmonary embolism[Title/Abstract])) OR (lung embolism[Title/Abstract])) OR (PE[Title/Abstract])) OR (thromboembolism[Title/Abstract])) OR (embolism[Title/Abstract])) OR (blood clot[Title/Abstract])

#5 ((thromboprophylaxis[Title/Abstract]) OR (prophyla*[Title/Abstract])) OR (prevent*[Title/Abstract])

#6 (((((((heparin[MeSH Terms]) OR (heparin, low-molecular-weight[MeSH Terms])) OR (anticoagulants[MeSH Terms])) OR (warfarin[MeSH Terms])) OR (aspirin[MeSH Terms])) OR (vena cava filters[MeSH Terms])) OR (stockings, compression[MeSH Terms])) OR (intermittent pneumatic compression devices[MeSH Terms])

#7 ((pentasaccharide*[Title/Abstract]) OR (fondaparinux[Title/Abstract])) OR (LMWH[Title/Abstract])

#8 (guideline[Publication Type]) OR (consensus development conference[Publication Type])

#9 ((guidelines as topic[MeSH Terms]) OR (consensus[MeSH Terms])) OR (consensus development conferences as topic[MeSH Terms])

#10 ((((guideline[Title/Abstract]) OR (guidance[Title/Abstract])) OR (recommendation[Title/Abstract])) OR (consensus[Title/Abstract])) OR (best practice[Title/Abstract])

#11 #1 OR #2

#12 #3 OR #4

#13 #5 OR #6 OR #7

#14 #8 OR #9 OR #10

#15 #11 AND #12 AND #13 AND #14

Determination of eligibility

Two reviewers (LH and J-YX) will independently screen and select the literature. First, they will determine whether the documents meets the inclusion criteria based on the titles and abstracts. After that, the reviewers will obtains the full texts of the documents, then read and filter out the eligible guidelines. Any disagreement between the two reviewers will be resolved through consensus or by the third reviewer (Z-KZ).

Data extraction

We will extract the following information of CPGs: (1) title; (2) year of publication; (3) authors; (4) country of development; (5) objective of CPG; (6) target users; (7) method used to collect the evidence; (8) grading methods for the evidence; (9) recommendation formulation method; (10) guideline validation methods; (11) intended users and (12) the specific content of the recommendations given, including the method of thromboprophylaxis, the timing of initiation, dose and duration, and target patients. In addition, we will record each score of items in AGREE-II and AGREE-REX with their reasons.

Quality assessment of CPGs

We will assess the quality of CPGs by AGREE-II.21 The tool was released in 2009 and includes 23 items in 6 domains (scope and purpose, stakeholder involvement, rigour of development, clarity of presentation, applicability and editorial independence), with two additional assessments for the guideline’s overall quality and whether it is recommended to use.

The quality of recommendations is evaluated using AGREE-REX.22 The tool was released in 2019 and included nine items in three domains (clinical applicability, values and preferences, and implementability). Each item has two assessment questions, one for quality evaluation (required) and another for suitability for use (optional). Overall judgement for all recommendations in CPG has two additional assessments: (1) I would recommend these recommendations for use in the appropriate context (required) and (2) I would recommend these recommendations for use in my context (optional).

Both AGREE-II and AGREE-REX quality evaluation items adopt a Likert scale of one to seven scores. The standardised scores for each domain are calculated according to the user manual,23 24 ranging from 0% to 100%. The higher the score obtained, the better the quality of the guideline in the relevant field. Considering that the method for evaluating the overall quality of the guideline remains controversial,25 we will not use a cut-off value to rate the overall quality but directly present the reviewers’ subjective judgement results.

Five reviewers (LH, J-YX, JL, HL and NN) conducted quality appraisals after systematically learning how to use AGREE-II and AGREE-REX. Reviewers use the online platform MY AGREE PLUS to use AGREE-II independently and blindly (, while the AGREE-REX assessment is performed offline.

Description and comparison of the recommendations

We plan to compare the recommendations included in the CPG, which will be extracted independently by two reviewers (D-BL and GL-W). The recommendations will be expectantly classified according to risk assessment, screening strategies, mechanical prophylaxis, chemical prophylaxis and other interventions to evaluate their scopes and differences in different CPGs. Discrepancies will be highlighted when there are conflicts between some recommendations.

Data analysis and presentation

All the data will be saved with Excel (Microsoft 365, Microsoftn, Redmond, Washington, USA) and analysed with SPSS statistical software (.26, IBM). For each domain of AGREE II and AGREE-REX, we will calculate the score by the following formula:

Scores for guidelines and recommendations will be described using the mean (SD) and median (IQR) (if needed). The intraclass correlation coefficient (ICC) will be used to evaluate the degree of agreement between reviewers. Based on Landis and Koch,26 an ICC value of 0.00–0.20 indicates slight agreement, 0.21–0.40 indicates fair agreement, 0.41–0.61 indicates moderate agreement, 0.61–0.80 indicates substantial agreement, 0.81–1.00 indicates almost perfect agreement. Differences in domain scores between CPGs will be compared using the Kruskal-Wallis H test. Significance level α=0.05 (two tailed).

Our study is expected to begin in November 2022 and complete in April 2023. We will explain any methodological changes in the study. The results are intended to be published in a peer-reviewed open journal.


Thromboprophylaxis in orthopaedic trauma patients is complicated due diverse risk factors. It is challenging to choose appropriate prevention methods for patients with coagulation abnormalities, lower limb injuries, etc. The use of anticoagulants may increase the risk of bleeding and wound complications in trauma patients,27–29 especially in the early postoperative period. Research in this field is scattered and controversial, and more work is needed to draw conclusions.30 There is still no consensus on evaluating evidence and recommendations between different guidelines, which increases the uncertainty of clinical decision making.31 Even in the relatively large number of hip fracture patients studied, physicians still believe that there is a lack of adequate clinical guidelines.32 We hope to evaluate the relevant guidelines for VTE prevention in orthopaedic trauma and critically appraise the quality of the guidelines and recommendations. To the best of our knowledge, there is currently no systematic review on the quality of English and Chinese orthopaedic trauma thromboprophylaxis guidelines.

It is a long process that costs plenty of workforce and resources for planning, formulating and disseminating a CPG, especially for high-quality CPGs. Rigorous methodology and regular updates play essential roles in maintaining the quality of the guidelines and practical application.33 Identifying high-quality recommendations will help us to prescribe appropriate thromboprophylaxis in the trauma population. It will also help discover knowledge gaps and new points for further research.34 We plan to summarise the divergent recommendations in such guidelines, which will be the main focus of future thromboprophylaxis research.

Our research may still have shortcomings. First, although we will adopted a comprehensive search strategy, only openly published documents will be obtained, and some grey literature may miss during the process. Second, we will only include CPGs published in Chinese and English, which may lead to an underestimation of the overall number of guidelines. Third, to obtain as comprehensive information as possible, we will not limit the start time for the publication of the guidelines. Those recommendations from earlier CPGs may not be consistent with current evidence.

Ethics statements

Patient consent for publication


The authors gratefully acknowledge the suggestions given by Mr. Lei Luo on the manuscript language editing.


Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.


  • Contributors Study design: LH, J-YX, NN and Z-KZ. Protocol drafting: LH, J-YX, JL, HL and D-BL. Manuscript reviewing and editing: LH, G-LW, NN and Z-KZ. All the authors have read, discussed, and approved the final version of the manuscript. NN and Z-KZ contributed equally to the manuscript.

  • Funding This research is supported by West China Nursing Discipline Development Special Fund Project, Sichuan University (No. HXHL20003).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.