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Guideline Summary
Guideline Title
Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Bibliographic Source(s)
National Institute for Health and Clinical Excellence (NICE). Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. London (UK): National Institute for Health and Clinical Excellence (NICE); 2012 Jun. 40 p. (Clinical guideline; no. 144). 
Guideline Status

This is the current release of the guideline.

Scope

Disease/Condition(s)
  • Venous thromboembolism (VTE)
  • Deep vein thrombosis (DVT)
  • Pulmonary embolism (PE)
  • Thrombophilia
  • Cancer

Note: This guideline does not cover:

  • Prophylaxis against VTE
  • DVT in the arms
  • Cerebral vein thrombosis
  • Splanchnic thrombosis
  • Retinal vein thrombosis
Guideline Category
Diagnosis
Management
Prevention
Screening
Treatment
Clinical Specialty
Emergency Medicine
Geriatrics
Hematology
Internal Medicine
Oncology
Preventive Medicine
Pulmonary Medicine
Radiology
Intended Users
Advanced Practice Nurses
Emergency Medical Technicians/Paramedics
Health Care Providers
Hospitals
Nurses
Patients
Physician Assistants
Physicians
Guideline Objective(s)

To provide best practice advice on the diagnosis and management of adults with venous thromboembolic diseases and the role of thrombophilia testing

Target Population

Adults with suspected or confirmed deep vein thrombosis (DVT) or pulmonary embolism (PE)

Within this population, the following groups have been identified as requiring special consideration: people with cancer, people who misuse intravenous drugs, residents of nursing homes and people with physical disabilities who have restricted movement following a venous thromboembolism and people with learning disabilities who require long-term medication taken at home. In addition first-degree relatives of people with inherited thrombophilia and venous thromboembolic diseases will be considered.

Note: The guideline does not cover children or young people aged under 18, or women who are pregnant.

Interventions and Practices Considered

Diagnosis/Evaluation

  1. Diagnostic investigations for deep vein thrombosis (DVT)
    • General medical history and a physical examination
    • Use of two-level DVT Wells score to estimate probability of DVT
    • Proximal leg vein ultrasound
    • D-dimer test
  2. Diagnostic investigations for pulmonary embolism (PE)
    • General medical history, physical examination, and chest x-ray
    • Use of two-level PE Wells score to estimate probability of PE
    • Computed tomography pulmonary angiogram (CTPA)
    • Ventilation/perfusion single photon emission computed tomography (V/Q SPECT) or V/Q planar scan
    • Proximal leg vein ultrasound
  3. Immediate interim anticoagulation therapy

Treatment/Management

  1. Low molecular weight heparin (LMWH)
  2. Fondaparinux
  3. Unfractionated heparin (UFH)
  4. Vitamin K antagonist
  5. Rivaroxaban
  6. Thrombolytic therapy
  7. Below-knee graduated compression stockings
  8. Temporary inferior vena caval filter
  9. Monitoring international normalized ratio (INR)
  10. Providing patients written and verbal information about anticoagulation
  11. Self-management and self-monitoring for patients treated with a vitamin K antagonist (not recommended)
  12. Investigations for cancer in patients with unprovoked DVT or PE
  13. Thrombophilia testing in patients with unprovoked DVT or PE
Major Outcomes Considered
  • Sensitivity, specificity, and positive and negative predictive value of diagnostic tests
  • Symptomatic and asymptomatic deep venous thrombosis rate
  • Symptomatic and asymptomatic pulmonary embolism rate
  • Three month venous thromboembolism (VTE) rate
  • VTE-related and all-cause mortality
  • Recurrent VTE rates
  • Major and minor bleeding and other adverse events of anticoagulation
  • Quality of life (validated scores)
  • Post thrombotic syndrome
  • Patient preference or patient views
  • Length of hospital stay
  • Cost-effectiveness

Methodology

Methods Used to Collect/Select the Evidence
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

Note from the National Guideline Clearinghouse (NGC): This guideline was developed by the National Clinical Guideline Centre (NCGC) on behalf of the National Institute for Health and Clinical Excellence (NICE). See the "Availability of Companion Documents" field for the full version of this guidance.

Clinical Literature Search

Systematic literature searches were undertaken to identify evidence within published literature in order to answer the review questions as per The Guidelines Manual 2009 (see the "Availability of Companion Documents" field). Clinical databases were searched using relevant medical subject headings, free-text terms and study type filters where appropriate. Studies published in languages other than English were not reviewed. Where possible, searches were restricted to articles published in English language. All searches were conducted on core databases, MEDLINE, Embase, Cinahl and The Cochrane Library. The additional subject specific database PsychInfo was used for the patient education question. All searches were updated on 1st August 2011. No papers after this date were considered.

Search strategies were checked by looking at reference lists of relevant key papers, checking search strategies in other systematic reviews and asking the Guideline Development Group (GDG) for known studies. The questions, the study types applied, the databases searched and the years covered can be found in Appendix D of the full version of the guideline.

During the scoping stage, a search was conducted for guidelines and reports on the websites listed below and on organisations relevant to the topic. Searching for grey literature or unpublished literature was not undertaken. All references sent by stakeholders were considered.

Inclusion/Exclusion

The inclusion and exclusion criteria were considered according to the PICO (patients, interventions, comparisons, outcomes) used in the protocols (see Appendix C of the full version of the guideline for full details.

A major consideration in determining the inclusion and exclusion criteria in the protocol was the applicability of the evidence to the guideline population. The populations included in the review may differ for each review question, depending on the applicability of the data.

Laboratory studies were excluded because the populations used (volunteers, animals or in vitro) are artificial and not comparable to the population the GDG was making recommendations for. These studies would undoubtedly be of very low quality as assessed by Grading of Recommendations Assessment Development Evaluation (GRADE) and therefore, low quality randomised controlled trials (RCTs), cohort studies or GDG consensus opinion was considered preferable.

Abstracts, posters, reviews, letters/editorials, foreign language publications and unpublished studies were excluded.

Health Economic Literature Search

Systematic literature searches were also undertaken to identify health economic evidence within published literature relevant to the review questions. The evidence was identified by conducting a broad search relating to the guideline population in the National Health Service economic evaluation database (NHS EED), the Health Economic Evaluations Database (HEED) and health technology assessment (HTA) databases with no date restrictions. Additionally, the search was run on MEDLINE and Embase, with a specific economic filter, from 2010, to ensure recent publications that had not yet been indexed by these databases were identified. Studies published in languages other than English were not reviewed. Where possible, searches were restricted to articles published in English language.

The search strategies for health economics are included in Appendix D of the full version of the guideline. All searches were updated on 1st August 2011. No papers published after this date were considered.

Inclusion/Exclusion

Full economic evaluations (studies comparing costs and health consequences of alternative courses of action: cost–utility, cost-effectiveness, cost-benefit and cost-consequence analyses) and comparative costing studies that addressed the review question in the relevant population were considered potentially applicable as economic evidence.

Studies that only reported cost per hospital (not per patient), or only reported average cost effectiveness without disaggregated costs and effects, were excluded. Abstracts, posters, reviews, letters/editorials, foreign language publications and unpublished studies were excluded. Studies judged to have an applicability rating of 'not applicable' were excluded (this included studies that took the perspective of a non-Organisation for Economic Co-operation and Development [OECD] country).

Remaining studies were prioritised for inclusion based on their relative applicability to the development of this guideline and the study limitations. For example, if a high quality, directly applicable UK analysis was available other less relevant studies may not have been included. Where exclusions occurred on this basis, this is noted in the relevant section.

For more details about the assessment of applicability and methodological quality see the economic evaluation checklist (Appendix H from the Guidelines Manual, 2009) and the health economics research protocol (Appendix C of the full version of the original guideline document [see the "Availability of Companion Documents" field]).

When no relevant economic analysis was found from the economic literature review, relevant UK NHS unit costs related to the compared interventions were presented to the GDG to inform the possible economic implication of the recommendation made.

Number of Source Documents

Not stated

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Overall Quality of Outcome Evidence in GRADE (Grading of Recommendations Assessment Development and Evaluation)

  • High - The Guideline Development Group (GDG) is very confident that the true effect lies close to that of the estimate of the effect.
  • Moderate - The GDG is moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
  • Low - Confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
  • Very low - The GDG has very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
Methods Used to Analyze the Evidence
Meta-Analysis
Review of Published Meta-Analyses
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence

Note from the National Guideline Clearinghouse (NGC): This guideline was developed by the National Clinical Guideline Centre (NCGC) on behalf of the National Institute for Health and Clinical Excellence (NICE). See the "Availability of Companion Documents" field for the full version of this guidance.

Clinical Effectiveness

Evidence of Effectiveness

The Research Fellow:

  • Identified potentially relevant studies for each review question from the relevant search results by reviewing titles and abstracts – full papers were then obtained.
  • Reviewed full papers against pre-specified inclusion/exclusion criteria to identify studies that addressed the review question in the appropriate population and reported on outcomes of interest (review protocols are included in Appendix C of the full version of the original guideline).
  • Critically appraised relevant studies using the appropriate checklist as specified in The Guidelines Manual 2009 (see "Availability of Companion Documents" field).
  • Extracted key information about the study's methods and results into evidence tables (evidence tables are included in Appendix E).
  • Generated summaries of the evidence by outcome (included in the relevant chapter write-ups of the full version of the original guideline):
    • Randomised studies: meta-analysed, where appropriate and reported in GRADE (Grading of Recommendations Assessment, Development and Evaluation) profiles (for clinical studies).
    • Observational studies: data presented as a range of values in GRADE profiles.
    • Qualitative studies: each study summarised in a table (available in Appendix E of the full version of the original guideline) where possible, and the quality of included studies assessed against the NICE quality checklists for qualitative studies. Key common themes between studies which were relevant to the review question were summarised and presented with a comment of the quality of studies contributing to the themes in the main guideline document. GRADE does not have a system for rating the quality of evidence for qualitative studies or surveys, and therefore there are no GRADE quality ratings for the themes identified.

Methods of Combining Clinical Studies

Data Synthesis for Intervention Reviews

Where possible, meta-analyses were conducted to combine the results of studies for each review question using Cochrane Review Manager (RevMan5) software. Fixed-effects (Mantel-Haenszel) techniques were used to calculate risk ratios (relative risk) for the binary outcomes. The continuous outcomes were analysed using an inverse variance method for pooling weighted mean differences and where the studies had different scales, standardised mean differences were used.

Statistical heterogeneity was assessed by considering the chi-squared test for significance at p <0.1 or an I-squared inconsistency statistic of >50% to indicate significant heterogeneity. Where there was heterogeneity and a sufficient number of studies, sensitivity analyses were conducted based on risk of bias and pre-specified subgroup analyses were carried out as defined in the protocol. Assessments of potential differences in effect between subgroups were based on the chi-squared tests for heterogeneity statistics between subgroups. If no sensitivity analysis was found to completely resolve statistical heterogeneity then a random effects (DerSimonian and Laird) model was employed to provide a more conservative estimate of the effect.

Data Synthesis for Diagnostic Test Accuracy Review

For diagnostic test accuracy studies, the outcomes reported depends on the review question and purpose of the test. The outcomes reported may include: sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio, pre- and post-test probabilities, or numbers of patients missed (false negative). In cases where the outcomes were not reported, 2 by 2 tables were constructed from raw data to allow calculation of these accuracy measures, and these are presented in the evidence tables (see Appendix E in the full version of the original guideline document [see the "Availability of Companion Documents" field]). "Test and treat" designs were considered as appropriate for some review questions, and the relevant patient important outcomes from these strategies were reported where appropriate.

As the meta-analysis methods of diagnostic outcome was a developing field and was not a standard analysis of NICE guidelines at the time of the guideline development, the data was not pooled. Results from diagnostic accuracy studies were entered into Review Manager 5.0, and the results are shown graphically.

Appraising the Quality of Evidence by Outcomes

After appropriate pooling of the results for each outcome across all studies, the quality of the evidence for each outcome was evaluated and presented using an adaptation of the Grading of Recommendations Assessment Development and Evaluation (GRADE) toolbox. The software (GRADEpro) developed by the international GRADE working group was used to record the assessment of the evidence quality for each outcome.

In this guideline, findings were summarised using two separate tables. The "Quality Assessment" table includes details of the quality assessment. Reporting or publication bias was only taken into consideration in the quality assessment and included in the Clinical Study Characteristics table if it is clear there was a risk of bias. Each outcome was examined separately for the quality elements listed and defined in Table 2 of the full version of the original guideline and each graded using the quality levels listed in Table 3 of the full guideline.

Grading the Quality of Clinical Evidence

After results were pooled, the overall quality of evidence for each outcome was considered. The following procedure was adopted when using GRADE:

A quality rating was assigned, based on the study design. Randomised controlled trials (RCTs) start HIGH and observational studies as LOW, uncontrolled case series as LOW or VERY LOW.

The rating was then downgraded for the specified criteria: study limitations, inconsistency, indirectness, imprecision and publication bias. These criteria are detailed in Table 5 of the full version of the original guideline document. Observational studies were upgraded if there was a large magnitude of effect, dose-response gradient, and if all plausible confounding would reduce a demonstrated effect or suggest a spurious effect when results showed no effect. Each quality element considered to have "serious" or "very serious" risk of bias was rated down -1 or -2 points respectively.

The downgraded/upgraded marks were then summed and the overall quality rating was revised. For example, all RCTs started as HIGH and the overall quality became MODERATE, LOW or VERY LOW if 1, 2 or 3 points were deducted respectively.

See the "Rating Scheme for the Strength of the Evidence" field for the overall quality of evidence.

See Section 3.3 in the full version of the original guideline document for additional information.

Cost-Effectiveness

NICE Economic Evidence Profiles

The NICE economic evidence profile has been used to summarise cost and cost-effectiveness estimates. The economic evidence profile shows, for each economic study, an assessment of applicability and methodological quality, with footnotes indicating the reasons for the assessment. These assessments were made by the health economist using the economic evaluation checklist from Appendix H, the Guidelines Manual. It also shows incremental costs, incremental outcomes (for example, quality-adjusted life years [QALYs]) and the incremental cost-effectiveness ratio from the primary analysis, as well as information about the assessment of uncertainty in the analysis. See Table 6 in the full version of the original guideline document (see the "Availability of Companion Documents" field) for more details.

If a non-UK study was included in the profile, the results were converted into pounds sterling using the appropriate purchasing power parity.

Where economic studies compare multiple strategies, results are not reported in the standard economic profile but are instead presented at the end of the relevant chapter in an alternative table. The study is summarised as a whole in a descriptive manner.

Undertaking New Health Economic Analysis

As well as reviewing the published economic literature for each review question, new economic analyses were undertaken by the Health Economist in priority areas. Priority areas for new health economic analysis were agreed by the Guideline Development Group (GDG) after formation of the review questions and consideration of the available health economic evidence.

Additional data for the analyses were identified as required through additional literature searches undertaken by the Health Economist, and discussion with the GDG. Model structure, inputs and assumptions were explained to and agreed by the GDG members during meetings, and they commented on subsequent revisions.

See Appendices H and I and Section 3.4 in the full version of the original guideline document (see the "Availability of Companion Documents" field) for details of the health economic analyses undertaken for the guideline.

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

Note from the National Guideline Clearinghouse (NGC): This guideline was developed by the National Clinical Guideline Centre (NCGC) on behalf of the National Institute for Health and Clinical Excellence (NICE). See the "Availability of Companion Documents" field for the full version of this guidance.

A multidisciplinary Guideline Development Group (GDG) comprising professional group members and consumer representatives of the main stakeholders developed this guideline. Staff from the National Clinical Guideline Centre provided methodological support and guidance for the development process. The team working on the guideline included a project manager, systematic reviewers, health economists and information scientists. They undertook systematic searches of the literature, appraised the evidence, conducted meta-analysis and cost effectiveness analysis where appropriate and drafted the guideline in collaboration with the GDG.

Developing the Review Questions and Outcomes

Review questions were developed in a PICO framework (patient, intervention, comparison and outcome) for intervention reviews, and with a framework of population, index tests, reference standard and target condition for reviews of diagnostic test accuracy. This was to guide the literature searching process and to facilitate the development of recommendations by the GDG.

As outlined in the NICE Guidelines Manual, review questions were developed based on the key clinical areas identified in the scope (see Appendix A of the full version of the original guideline). These were drafted by the NCGC technical team and refined and validated by the GDG through discussions to ensure that the right review questions are identified.

Often, the GDG found that several review questions can be generated for a single area within the scope. However, only 15 to 20 questions can be reasonably managed within the usual time frame of full clinical guideline development (18 months). Since it was not possible to cover all potentially important aspects, the GDG had to consider the relative importance of these and prioritise areas for developing review questions. This decision should take into consideration factors such as whether the area is a key clinical issue for the National Health Service (NHS), patient safety, cost (to the NHS), equality and variations in practice.

Review questions and outcome measures examined in this guideline are detailed in Table 1 of the full version of the original guideline and protocols can be found in Appendix C of the full guideline. Areas where no review questions were made include risk stratification of patients with pulmonary embolism (PE), factors or tests results (e.g., D-dimer tests) associated with risk of recurrence of venous thromboembolic disease (VTE), where patients should be managed and whether isolated calf vein deep vein thrombosis (DVT) should be treated.

Developing Recommendations

Over the course of the guideline development process, the GDG was presented with:

  • Evidence tables of the clinical and economic evidence reviewed from the literature. All evidence tables are in Appendices E and F of the full version of the original guideline document.
  • Summary of clinical and economic evidence and quality (as presented in Chapters 5 to 14 of the full version of the original guideline document).
  • Forest plots (Appendix G).
  • A description of the methods and results of the cost-effectiveness analysis undertaken for the guideline (Appendices H and I).

Recommendations were drafted on the basis of the GDG interpretation of the available evidence, taking into account the balance of benefits and harms, quality of evidence, and costs. When clinical and economic evidence was of poor quality, conflicting or absent, the GDG drafted recommendations based on consensus. Expert advisors were invited to provide advice on how to interpret the identified evidence. The considerations for making consensus based recommendations include the balance between potential harms and benefits, economic or implications compared to the benefits, current practices, recommendations made in other relevant guidelines, patient preferences and equality issues. The consensus recommendations were made through discussions in the GDG, or methods of formal consensus were applied. The GDG also considered whether the uncertainty was sufficient to justify delaying making a recommendation to await further research, taking into account the potential harm of failing to make a clear recommendation.

Rating Scheme for the Strength of the Recommendations

Not applicable

Cost Analysis

Cost-effectiveness Criteria

In general, an intervention was considered to be cost effective if either of the following criteria applied (given that the estimate was considered plausible):

  • The intervention dominated other relevant strategies (that is, it was both less costly in terms of resource use and more clinically effective compared with all the other relevant alternative strategies), or
  • The intervention cost less than £20,000 per quality-adjusted life-year (QALY) gained compared with the next best strategy.

If the GDG recommended an intervention that was estimated to cost more than £20,000 per QALY gained, or did not recommend one that was estimated to cost less than £20,000 per QALY gained, the reasons for this decision are discussed explicitly in the "from evidence to recommendations" section of the relevant chapter of the full version of the original guideline with reference to issues regarding the plausibility of the estimate or to the factors set out in the 'Social value judgements: principles for the development of NICE guidance.'

If a study reported the cost per life year gained but not QALYs, the cost per QALY gained was estimated by multiplying by an appropriate utility estimate to aid interpretation. The estimated cost per QALY gained is reported in the economic evidence profile with a footnote detailing the life-years gained and the utility value used. When QALYs or life years gained are not used in the analysis, results are difficult to interpret unless one strategy dominates the others with respect to every relevant health outcome and cost.

See Appendices H-I of the full version of the original guideline document for details of the health economic analyses undertaken for the guideline.

Method of Guideline Validation
External Peer Review
Internal Peer Review
Description of Method of Guideline Validation

The guideline was validated through two consultations.

  1. The first draft of the guideline (the full guideline, National Institute for Health and Clinical Excellence [NICE] guideline, and Quick Reference Guide) were consulted with Stakeholders and comments were considered by the Guideline Development Group (GDG)
  2. The final consultation draft of the Full guideline, the NICE guideline and the Information for the Public were submitted to stakeholders for final comments.

The final draft was submitted to the Guideline Review Panel for review prior to publication.

Recommendations

Major Recommendations

Note from the National Guideline Clearinghouse (NGC): This guideline was developed by the National Clinical Guideline Centre on behalf of the National Institute for Health and Clinical Excellence (NICE). See the "Availability of Companion Documents" field for the full version of this guidance.

To ensure comprehensive management and continuity when developing a programme of care for patients who are at risk of or who develop venous thromboembolism (VTE), users of this guideline are encouraged to refer to the NICE guidance:

Diagnosis

Diagnostic Investigations for Deep Vein Thrombosis (DVT)

If a patient presents with signs or symptoms of DVT, carry out an assessment of their general medical history and a physical examination to exclude other causes.

If DVT is suspected, use the two-level DVT Wells score (see Table 1 in the original guideline document) to estimate the clinical probability of DVT.

Offer patients in whom DVT is suspected and with a likely two-level DVT Wells score either:

  • A proximal leg vein ultrasound scan carried out within 4 hours of being requested and, if the result is negative, a D-dimer test or
  • A D-dimer test and an interim 24-hour dose of a parenteral anticoagulant (if a proximal leg vein ultrasound scan cannot be carried out within 4 hours) and a proximal leg vein ultrasound scan carried out within 24 hours of being requested.

Repeat the proximal leg vein ultrasound scan 6 to 8 days later for all patients with a positive D-dimer test and a negative proximal leg vein ultrasound scan.

Offer patients in whom DVT is suspected and with an unlikely two-level DVT Wells score (see Table 1 in the original guideline document) a D-dimer test and if the result is positive offer either:

  • A proximal leg vein ultrasound scan carried out within 4 hours of being requested or
  • An interim 24-hour dose of a parenteral anticoagulant (if a proximal leg vein ultrasound scan cannot be carried out within 4 hours) and a proximal leg vein ultrasound scan carried out within 24 hours of being requested.

Diagnose DVT and treat (see Treatment section below) patients with a positive proximal leg vein ultrasound scan.

Take into consideration alternative diagnoses in patients with:

  • An unlikely two-level DVT Wells score (see Table 1 in the original guideline document) and
    • A negative D-dimer test or
    • A positive D-dimer test and a negative proximal leg vein ultrasound scan
  • A likely two-level DVT Wells score and
    • A negative proximal leg vein ultrasound scan and a negative D-dimer test or
    • A repeat negative proximal leg vein ultrasound scan

Advise patients in these two groups that it is not likely they have DVT, and discuss with them the signs and symptoms of DVT and when and where to seek further medical help.

Diagnostic Investigations for Pulmonary Embolism (PE)

If a patient presents with signs or symptoms of PE, carry out an assessment of their general medical history, a physical examination and a chest X-ray to exclude other causes.

If PE is suspected, use the two-level PE Wells score (see Table 2 in the original guideline document) to estimate the clinical probability of PE.

Offer patients in whom PE is suspected and with a likely two-level PE Wells score either:

  • An immediate computed tomography pulmonary angiogram (CTPA) or
  • Immediate interim parenteral anticoagulant therapy followed by a CTPA, if a CTPA cannot be carried out immediately

Consider a proximal leg vein ultrasound scan if the CTPA is negative and DVT is suspected.

Offer patients in whom PE is suspected and with an unlikely two-level PE Wells score (see Table 2 in the original guideline document) a D-dimer test and if the result is positive offer either:

  • An immediate CTPA or
  • Immediate interim parenteral anticoagulant therapy followed by a CTPA, if a CTPA cannot be carried out immediately

For patients who have an allergy to contrast media, or who have renal impairment, or whose risk from irradiation is high:

  • Assess the suitability of a ventilation/perfusion single photon emission computed tomography (V/Q SPECT) scan or, if a V/Q SPECT scan is not available, a V/Q planar scan, as an alternative to CTPA.
  • If offering a V/Q SPECT or planar scan that will not be available immediately, offer immediate interim parenteral anticoagulant therapy.

Diagnose PE and treat (see the Treatment section below) patients with a positive CTPA or in whom PE is identified with a V/Q SPECT or planar scan.

Take into consideration alternative diagnoses in the following two groups of patients:

  • Patients with an unlikely two-level PE Wells score (see Table 2 in the original guideline document) and either:
    • A negative D-dimer test or
    • A positive D-dimer test and a negative CTPA
  • Patients with a likely two-level PE Wells score and both:
    • A negative CTPA and
    • No suspected DVT

Advise these patients that it is not likely they have PE and discuss with them the signs and symptoms of PE, and when and where to seek further medical help.

Patients with Signs or Symptoms of Both Deep Vein Thrombosis and Pulmonary Embolism

If a patient presents with signs or symptoms of both DVT (for example a swollen and/or painful leg) and PE (for example chest pain, shortness of breath or haemoptysis), carry out initial diagnostic investigations for either DVT or PE, basing the choice of diagnostic investigations on clinical judgement.

Treatment

Pharmacological Interventions

Deep Vein Thrombosis or Pulmonary Embolism

Offer a choice of low molecular weight heparin (LMWH) or fondaparinux to patients with confirmed proximal DVT or PE, taking into account comorbidities, contraindications and drug costs, with the following exceptions:

  • For patients with severe renal impairment or established renal failure (estimated glomerular filtration rate [eGFR] <30 ml/min/1.73 m2) offer unfractionated heparin (UFH) with dose adjustments based on the APTT (activated partial thromboplastin time) or LMWH with dose adjustments based on an anti-Xa assay.
  • For patients with an increased risk of bleeding consider UFH.
  • For patients with PE and haemodynamic instability, offer UFH and consider thrombolytic therapy (see recommendations below on pharmacological systemic thrombolytic therapy in pulmonary embolism).

Start the LMWH, fondaparinux or UFH as soon as possible and continue it for at least 5 days or until the international normalised ratio (INR) (adjusted by a vitamin K antagonist [VKA]; see recommendation on VKA for patients with confirmed proximal DVT or PE below) is 2 or above for at least 24 hours, whichever is longer.

Offer LMWH to patients with active cancer and confirmed proximal DVT or PE, and continue the LMWH for 6 months. (At the time of publication [June 2012] some types of LMWH do not have a UK marketing authorisation for 6 months of treatment of DVT or PE in patients with cancer. Prescribers should consult the summary of product characteristics for the individual LMWH and make appropriate adjustments for severe renal impairment or established renal failure. Informed consent for off-label use should be obtained and documented.)  At 6 months, assess the risks and benefits of continuing anticoagulation. (Although this use is common in UK clinical practice, at the time of publication [June 2012] none of the anticoagulants has a UK marketing authorisation for the treatment of DVT or PE beyond 6 months in patients with cancer. Informed consent for off-label use should be obtained and documented.)

Offer a VKA to patients with confirmed proximal DVT or PE within 24 hours of diagnosis and continue the VKA for 3 months. At 3 months, assess the risks and benefits of continuing VKA treatment.

Offer a VKA beyond 3 months to patients with an unprovoked PE, taking into account the patient's risk of VTE recurrence and whether they are at increased risk of bleeding. Discuss with the patient the benefits and risks of extending their VKA treatment.

Consider extending the VKA beyond 3 months for patients with unprovoked proximal DVT if their risk of VTE recurrence is high and there is no additional risk of major bleeding. Discuss with the patient the benefits and risks of extending their VKA treatment.

Rivaroxaban

NICE is developing technology appraisal guidance on rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism (publication expected July 2012).

Thrombolytic Therapy

Deep Vein Thrombosis

Consider catheter-directed thrombolytic therapy for patients with symptomatic iliofemoral DVT who have:

  • Symptoms of less than 14 days' duration and
  • Good functional status and
  • A life expectancy of 1 year or more and
  • A low risk of bleeding

Pulmonary Embolism

Consider pharmacological systemic thrombolytic therapy for patients with PE and haemodynamic instability (see also recommendation on pharmacological interventions for DVT and PE above).

Do not offer pharmacological systemic thrombolytic therapy to patients with PE and haemodynamic stability (see also recommendation on pharmacological interventions for DVT and PE above).

Mechanical Interventions

Proximal Deep Vein Thrombosis or Pulmonary Embolism

Offer below-knee graduated compression stockings with an ankle pressure greater than 23 mmHg to patients with proximal DVT a week after diagnosis or when swelling is reduced sufficiently and if there are no contraindications, and:

  • Advise patients to continue wearing the stockings for at least 2 years
  • Ensure that the stockings are replaced two or three times per year or according to the manufacturer's instructions
  • Advise patients that the stockings need to be worn only on the affected leg or legs

(Prescribers should refer to specific product information and contraindications before offering graduated compression stockings.)

Offer temporary inferior vena caval filters to patients with proximal DVT or PE who cannot have anticoagulation treatment, and remove the inferior vena caval filter when the patient becomes eligible for anticoagulation treatment.

Consider inferior vena caval filters for patients with recurrent proximal DVT or PE despite adequate anticoagulation treatment only after considering alternative treatments such as:

  • Increasing target INR to 3–4 for long-term high-intensity oral anticoagulant therapy or
  • Switching treatment to LMWH

Ensure that a strategy for removing the inferior vena caval filter at the earliest possible opportunity is planned and documented when the filter is placed, and that the strategy is reviewed regularly.

Patient Information

Give patients having anticoagulation treatment verbal and written information about:

  • How to use anticoagulants
  • Duration of anticoagulation treatment
  • Possible side effects of anticoagulant treatment and what to do if these occur
  • The effects of other medications, foods and alcohol on oral anticoagulation treatment
  • Monitoring their anticoagulant treatment
  • How anticoagulants may affect their dental treatment
  • Taking anticoagulants if they are planning pregnancy or become pregnant
  • How anticoagulants may affect activities such as sports and travel
  • When and how to seek medical help

Provide patients who are having anticoagulation treatment with an "anticoagulant information booklet" and an "anticoagulant alert card" and advise them to carry the "anticoagulant alert card" at all times.

Be aware that heparins are of animal origin and this may be of concern to some patients (see "Religion or belief: a practical guide for the National Health Service [NHS]"). For patients who have concerns about using animal products, consider offering synthetic alternatives based on clinical judgement after discussing their suitability, advantages and disadvantages with the patient. (This recommendation is from Venous thromboembolismin adults admitted to hospital: reducing the risk. Reducing the risk of venous thromboembolism [deep vein thrombosis and pulmonary embolism] in patients admitted to hospital [NICE clinical guideline 92; see the NGC summary]).

Advise patients about the correct application and use of below-knee graduated compression stockings, how long they should be worn and when they should be replaced.

Self-management and Self-monitoring for Patients Treated with a Vitamin K Antagonist

Do not routinely offer self-management or self-monitoring of INR to patients who have had DVT or PE and are having treatment with a VKA.

Investigations for Cancer

Offer all patients diagnosed with unprovoked DVT or PE who are not already known to have cancer the following investigations for cancer:

  • A physical examination (guided by the patient's full history) and
  • A chest X-ray and
  • Blood tests (full blood count, serum calcium and liver function tests) and
  • Urinalysis

Consider further investigations for cancer with an abdomino-pelvic CT scan (and a mammogram for women) in all patients aged over 40 years with a first unprovoked DVT or PE who do not have signs or symptoms of cancer based on initial investigation (see the recommendation above).

Thrombophilia Testing

Do not offer thrombophilia testing to patients who are continuing anticoagulation treatment.

Consider testing for antiphospholipid antibodies in patients who have had unprovoked DVT or PE if it is planned to stop anticoagulation treatment.

Consider testing for hereditary thrombophilia in patients who have had unprovoked DVT or PE and who have a first-degree relative who has had DVT or PE if it is planned to stop anticoagulation treatment.

Do not offer thrombophilia testing to patients who have had provoked DVT or PE.

Do not routinely offer thrombophilia testing to first-degree relatives of people with a history of DVT or PE and thrombophilia.

Clinical Algorithm(s)

Two algorithms are provided in the full version of the original guideline document for:

  • Diagnosis of deep vein thrombosis (DVT)
  • Diagnosis of pulmonary embolism (PE)

In addition, A NICE pathway for venous thromboembolism is provided at the National Institute for Health and Clinical Excellence (NICE) Web site External Web Site Policy.

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of evidence supporting the recommendations is not specifically stated.

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Appropriate management of patients with venous thromboembolic diseases

Potential Harms
  • Adverse effects from contrast media (e.g., renal impairment and contrast media allergy) used in imaging procedures
  • Low molecular weight heparin (LMWH) and fondaparinux should be used with caution for people with renal impairment, and unfractionated heparin should be considered as an alternative
  • Risk of bleeding from anticoagulation
  • Skin disorders and irritation and discomfort from graduated compression stockings

Contraindications

Contraindications

The contraindications to use of graduated compression stockings include:

  • Suspected or proven peripheral arterial disease
  • Peripheral arterial bypass grafting
  • Peripheral neuropathy or other causes of sensory impairment
  • Any local conditions in which stockings may cause damage, for example fragile 'tissue paper' skin, dermatitis, gangrene or recent skin graft
  • Known allergy to material of manufacture
  • Cardiac failure
  • Severe leg oedema or pulmonary oedema from congestive heart failure
  • Unusual leg size or shape
  • Major limb deformity preventing correct fit

Qualifying Statements

Qualifying Statements
  • This guidance represents the view of the National Institute for Health and Clinical Excellence (NICE), which was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer, and informed by the summary of product characteristics of any drugs they are considering.
  • Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.
  • The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients. This guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are marked with a footnote in the recommendations.

Implementation of the Guideline

Description of Implementation Strategy

National Institute for Health and Clinical Excellence (NICE) has developed tools to help organisations implement this guidance (see http://guidance.nice.org.uk/CG144 External Web Site Policy; see also "Availability of Companion Documents" field).

Key Priorities for Implementation

The following recommendations have been identified as priorities for implementation.

Diagnosis

Diagnostic Investigations for Deep Vein Thrombosis (DVT)

If a patient presents with signs or symptoms of DVT, carry out an assessment of their general medical history and a physical examination to exclude other causes.

Offer patients in whom DVT is suspected and with a likely two-level DVT Wells score either:

  • A proximal leg vein ultrasound scan carried out within 4 hours of being requested and, if the result is negative, a D-dimer test or
  • A D-dimer test and an interim 24-hour dose of a parenteral anticoagulant (if a proximal leg vein ultrasound scan cannot be carried out within 4 hours) and a proximal leg vein ultrasound scan carried out within 24 hours of being requested.

Repeat the proximal leg vein ultrasound scan 6 to 8 days later for all patients with a positive D-dimer test and a negative proximal leg vein ultrasound scan.

Offer patients in whom DVT is suspected and with an unlikely two-level DVT Wells score a D-dimer test and if the result is positive offer :

  • A proximal leg vein ultrasound scan carried out within 4 hours of being requested or
  • An interim 24-hour dose of a parenteral anticoagulant (if a proximal leg vein ultrasound scan cannot be carried out within 4 hours) and a proximal leg vein ultrasound scan carried out within 24 hours of being requested.

 

Diagnostic Investigations for Pulmonary Embolism (PE)

Offer patients in whom PE is suspected and with a likely two-level PE Wells score either:

 

  • An immediate computed tomography pulmonary angiogram (CTPA) or
  • Immediate interim parenteral anticoagulant therapy followed by a CTPA, if a CTPA cannot be carried out immediately.

 

Consider a proximal leg vein ultrasound scan if the CTPA is negative and DVT is suspected.

Offer patients in whom PE is suspected and with an unlikely two-level PE Wells score a D-dimer test and if the result is positive offer either:

 

  • An immediate CTPA or
  • Immediate interim parenteral anticoagulant therapy followed by a CTPA, if a CTPA cannot be carried out immediately

 

Treatment

Pharmacological Interventions

Deep Vein Thrombosis or Pulmonary Embolism

Offer a choice of low molecular weight heparin (LMWH) or fondaparinux to patients with confirmed proximal DVT or PE, taking into account comorbidities, contraindications and drug costs, with the following exceptions:

 

  • For patients with severe renal impairment or established renal failure (estimated glomerular filtration rate [eGFR] <30 ml/min/1.73 m2) offer unfractionated heparin (UFH) with dose adjustments based on the APTT (activated partial thromboplastin time) or LMWH with dose adjustments based on an anti-Xa assay.
  • For patients with an increased risk of bleeding consider UFH.
  • For patients with PE and haemodynamic instability, offer UFH and consider thrombolytic therapy (see recommendations on pharmacological systemic thrombolytic therapy in pulmonary embolism in the "Major Recommendations" field).

 

Start the LMWH, fondaparinux or UFH as soon as possible and continue it for at least 5 days or until the international normalised ratio (INR) (adjusted by a vitamin K antagonist [VKA]) is 2 or above for at least 24 hours, whichever is longer. (See the recommendation on VKA for patients with confirmed proximal DVT or PE in the "Major Recommendations" field).

 

  • Offer LMWH to patients with active cancer and confirmed proximal DVT or PE, and continue the LMWH for 6 months. (At the time of publication [June 2012] some types of LMWH do not have a UK marketing authorisation for 6 months of treatment of DVT or PE in patients with cancer. Prescribers should consult the summary of product characteristics for the individual LMWH and make appropriate adjustments for severe renal impairment or established renal failure. Informed consent for off-label use should be obtained and documented.) At 6 months, assess the risks and benefits of continuing anticoagulation. (Although this use is common in UK clinical practice, at the time of publication [June 2012] none of the anticoagulants has a UK marketing authorisation for the treatment of DVT or PE beyond 6 months in patients with cancer. Informed consent for off-label use should be obtained and documented.)
  • Offer a VKA beyond 3 months to patients with an unprovoked PE, taking into account the patient's risk of VTE recurrence and whether they are at increased risk of bleeding. Discuss with the patient the benefits and risks of extending their VKA treatment.
  • Consider extending the VKA beyond 3 months for patients with unprovoked proximal DVT if their risk of VTE recurrence is high and there is no additional risk of major bleeding. Discuss with the patient the benefits and risks of extending their VKA treatment.

 

Thrombolytic Therapy

Deep Vein Thrombosis

Consider catheter-directed thrombolytic therapy for patients with symptomatic iliofemoral DVT who have:

 

  • Symptoms of less than 14 days' duration and
  • Good functional status and
  • A life expectancy of 1 year or more and
  • A low risk of bleeding

 

Mechanical Interventions

Proximal Deep Vein Thrombosis or Pulmonary Embolism

Offer below-knee graduated compression stockings with an ankle pressure greater than 23 mmHg to patients with proximal DVT a week after diagnosis or when swelling is reduced sufficiently and if there are no contraindications, and:

 

  • Advise patients to continue wearing the stockings for at least 2 years
  • Ensure that the stockings are replaced two or three times per year or according to the manufacturers' instructions.
  • Advise patients that the stockings need to be worn only on the affected leg or legs.

 

(Prescribers should refer to specific product information and contraindications before offering graduated compression stockings.)

Investigations for Cancer

Consider further investigations for cancer with an abdomino-pelvic CT scan (and a mammogram for women) in all patients aged over 40 years with a first unprovoked DVT or PE who do not have signs or symptoms of cancer based on initial investigation.

Implementation Tools
Audit Criteria/Indicators
Clinical Algorithm
Patient Resources
Resources
Slide Presentation
Staff Training/Competency Material
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Getting Better
Living with Illness
IOM Domain
Effectiveness
Patient-centeredness

Identifying Information and Availability

Bibliographic Source(s)
National Institute for Health and Clinical Excellence (NICE). Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. London (UK): National Institute for Health and Clinical Excellence (NICE); 2012 Jun. 40 p. (Clinical guideline; no. 144). 
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2012 Jun 27
Guideline Developer(s)
National Clinical Guideline Centre - National Government Agency [Non-U.S.]
Source(s) of Funding

National Institute for Health and Clinical Excellence

Guideline Committee

Guideline Development Group

Composition of Group That Authored the Guideline

Guideline Development Group Members: Gerard Stansby, Professor of Vascular Surgery, Freeman Hospital and Newcastle University; Roshan Agarwal, Senior Lecturer/Honorary Consultant Medical Oncologist, Imperial College London; Susan Ballard, Patient/carer member; David Berridge, Consultant Vascular Surgeon, Leeds General Infirmary; Christian Clark, Patient and carer member, Member of the Atrial Fibrillation Task Force; Richard Day, Consultant Physician (Geriatrics), Poole Hospital NHS Foundation Trust; Hayley Flavell, Anticoagulant and Thrombosis Consultant Nurse, Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust; Scott Harrison, Lead Pharmacist Anticoagulation, Oxford University Hospital NHS Trust; Beverley Hunt, Professor of Thrombosis and Haemostasis, King's College, London and Medical Director of Lifeblood; David Keeling, Consultant Haematologist, Oxford University Hospitals NHS Trust; Nigel Langford, Acute Medical Physician, Sandwell and West Birmingham NHS Trust, City Hospital, Birmingham; Steven Moser, Consultant Radiologist, Imperial College Healthcare NHS Trust, London; Kat Noble, General Practitioner with a specialist interest in Emergency Care, NHS County Durham; Karen Sheares, Respiratory Consultant with an interest in pulmonary vascular diseases, Papworth Hospital NHS Foundation Trust

Financial Disclosures/Conflicts of Interest

At the start of the guideline development process all Guideline Development Group (GDG) members declared interests including consultancies, fee-paid work, share-holdings, fellowships and support from the healthcare industry. At all subsequent GDG meetings, members declared arising conflicts of interest, which were also recorded.

Members were either required to withdraw completely or for part of the discussion if their declared interest made it appropriate. The details of declared interests and the actions taken are shown in Appendix B of the full version of the original guideline document.

Guideline Status

This is the current release of the guideline.

Guideline Availability
Availability of Companion Documents

The following are available:

  • Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. Full guideline. London (UK): National Institute for Health and Clinical Excellence (NICE); 2012 June. 244 p. (Clinical guideline; no. 144). Electronic copies: Available in Portable Document Format (PDF) from the National Institute for Health and Clinical Excellence (NICE) Web site External Web Site Policy.
  • Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. Appendices to full version. London (UK): National Institute for Health and Clinical Excellence (NICE); 2012 June. 653 p. (Clinical guideline; no. 144). Electronic copies: Available in Portable Document Format (PDF) from the NICE Web site External Web Site Policy.
  • Venous thromboembolic diseases. Clinical case scenarios. London (UK): National Institute for Health and Clinical Excellence (NICE); 2012 June. (Clinical guideline; no. 144). Electronic copies: Available in Portable Document Format (PDF) and Powerpoint format from the NICE Web site External Web Site Policy.
  • Venous thromboembolic diseases. Clinical audit tools. London (UK): National Institute for Health and Clinical Excellence (NICE); 2012 June. (Clinical guideline; no. 144). Electronic copies: Available from the NICE Web site External Web Site Policy.
  • Venous thromboembolic diseases. Baseline assessment tool. London (UK): National Institute for Health and Clinical Excellence (NICE); 2012 June. (Clinical guideline; no. 144). Electronic copies: Available from the NICE Web site External Web Site Policy.
  • Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. Costing statement. London (UK): National Institute for Health and Clinical Excellence (NICE); 2012 June. 17 p. (Clinical guideline; no. 144). Electronic copies: Available in Portable Document Format (PDF) from the NICE Web site External Web Site Policy.
  • Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. Slide sets. London (UK): National Institute for Health and Clinical Excellence (NICE); 2012 June. (Clinical guideline; no. 144). Electronic copies: Available from the NICE Web site External Web Site Policy.
  • Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. Education Resources. London (UK): National Institute for Health and Clinical Excellence (NICE); 2012 June. (Clinical guideline; no. 144). Electronic copies: Available from the NICE Web site External Web Site Policy.
  • Venous thromboembolism overview. NICE pathway. London (UK): National Institute for Health and Clinical Excellence (NICE); 2012 June. (Clinical guideline; no. 144). Available from the NICE Web site External Web Site Policy.
  • Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. Two-level Wells score: templates for deep vein thrombosis and pulmonary embolism London (UK): National Institute for Health and Clinical Excellence (NICE); 2012 June. 6 p. (Clinical guideline; no. 144). Electronic copies: Electronic copies: Available from the NICE Web site External Web Site Policy.
  • The guidelines manual 2009. London (UK): National Institute for Health and Clinical Excellence (NICE); 2009 Jan. Electronic copies: Available in Portable Document Format (PDF) from the NICE Archive Web site External Web Site Policy.
Patient Resources

The following is available:

Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information, it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.

NGC Status

This summary was completed by ECRI Institute on September 5, 2012. This summary was updated by ECRI Institute on March 10, 2014 following the U.S. Food and Drug Administration advisory on Low Molecular Weight Heparins.

The National Institute for Health and Clinical Excellence (NICE) has granted the National Guideline Clearinghouse (NGC) permission to include summaries of their clinical guidelines with the intention of disseminating and facilitating the implementation of that guidance. NICE has not yet verified this content to confirm that it accurately reflects that original NICE guidance and therefore no guarantees are given by NICE in this regard. All NICE clinical guidelines are prepared in relation to the National Health Service in England and Wales. NICE has not been involved in the development or adaptation of NICE guidance for use in any other country. The full versions of all NICE guidance can be found at www.nice.org.uk External Web Site Policy.

Copyright Statement

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.

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