Dr Anil Kamat shows how the NICE interactive pathway on VTE distils current guidance and support for the diagnosis, treatment, and management of this preventable condition

kamat anil

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Read this article to learn more about:

  • the vital role of primary care in VTE management and the challenges
  • appropriate mechanical and pharmacological interventions for VTE prophylaxis and treatment
  • information that should be provided to patients.

Key points

GP commissioning messages

 

Venous thromboembolism (VTE) is a significant public health concern associated with severe morbidity and mortality. It manifests predominantly as deep vein thrombosis (DVT) and pulmonary embolism (PE). Other sites of atypical thrombosis include porto-hepatic, mesenteric, and cerebral sinus systems. Mortality in VTE stems predominantly from haemodynamic instability resulting from severe PE or vital organ failure, for example from cerebral sagittal sinus thrombosis. Post thrombotic syndrome (PTS), a complication of DVT, manifests as chronic limb swelling, pain, dilated superficial veins, occasional leg ulceration, and impaired mobility. It can occur in up to 25% of patients with DVT, often as a result of inadequate anticoagulation and the non-use of thromboembolic deterrent stockings. 1 Efficient management of VTE can reduce avoidable deaths, long-term disability, and chronic ill health

Over the past decade, numerous NICE guidelines have been issued following a highly critical House of Commons report in 2005 (see below),1 which highlighted systemic failures in the management of VTE both in primary and secondary care. This article aims to summarise the recommendations from these guidelines to aid implementation in primary care.

Venous thromboembolism—individual and societal impact

The 2005 House of Commons report1 estimated that between 25,000 and 32,000 deaths each year were attributable to PE/VTE, alarmingly a higher number than the combined deaths from breast cancer, AIDS, and traffic accidents, and many times more than deaths from MRSA and all hospital-acquired infections. The report estimated the societal cost to the UK of managing VTE at £640 million annually.

The incidence of DVT is estimated to be approximately twice that of PE.2 At an individual level, VTE—a largely preventable disease—causes not only physical harm but also imposes financial burdens on patients, their dependants, and society arising from time taken off work; if VTE is complicated by PTS, chronic ill-health and disability with long-term economic impact can result.

Efficient management of VTE with appropriate diagnostic tools, antithrombotic agents, and mechanical prophylaxis can contribute immensely to reducing VTE-associated morbidity and mortality.

VTE management in primary care

Primary care plays a vital role in VTE management, both in prevention and treatment.

Primary care pathways have to be clearly defined for:

  • diagnosis and treatment of VTE
  • secondary care referrals
  • anticoagulant treatment guided by individual circumstances, including the possible options for use of novel oral anticoagulant (NOAC) agents
  • long-term management of:
    • secondary prevention
    • sequelae of VTE, including PTS
  • patient education.

With GP-based commissioning, several of the primary care consortiums have attempted to address these issues. The different aspects of VTE management vary across England, depending on local commissioning arrangements for:

  • diagnostics (laboratory and radiology)
  • funding for NOAC agents
  • anticoagulation clinics for vitamin K antagonists (e.g. warfarin)
  • uptake of NICE guidance and pathways.

NICE Pathway for prevention of VTE

The NICE Venous thromboembolism pathway3 (see here) provides guidance for the diagnosis and management of VTE. The pathway brings together all NICE guidance, quality standards, and supporting materials on venous thromboembolism.4,5,6,7

Diagnosis and assessment

Clinical suspicion of VTE should be based on the two-level Wells scoring system for DVT and PE.8,9,10 The next step, in the event of a DVT, is an urgent (i.e. given within 4 hours)7 proximal leg vein ultrasound scan; for suspected PE, computed tomography pulmonary angiogram (CTPA) is required (NB: for patients who are allergic to contrast media, or who have renal impairment, or whose risk from irradiation is high, ventilation/ perfusion single photon emission computed tomography [V/Q SPECT] or planar scan should be requested, if available).

If urgent radiology access is not available, a D-dimer test (in suspected DVT) should be performed and immediate interim parenteral anticoagulant therapy offered. D-dimer tests have limitations and vary in their sensitivity and specificity but overall they carry a high negative predictive value. There are, however, several clinical situations when D-dimer should not be performed due to the high likelihood of false positive (e.g. pregnancy, previous VTE, recent surgery, active cancer, and ongoing anticoagulant treatment).11

A proximal leg vein ultrasound scan or CTPA (or V/Q SPECT or planar scan) should be performed within 24 hours following initial D-dimer testing and an interim 24-hour dose of a parenteral anticoagulant. Treatment may then be initiated, depending on the result. In the event of discordant results with negative radiology and positive D-dimer, a repeat ultrasound scan/CT scan may be performed within 6–8 days and treatment initiated if the result is positive. If the result is again negative, reassure the patient, consider an alternative diagnosis, and inform the patient about the signs and symptoms of DVT.

In case of suspected PE with negative radiology, perform a proximal leg vein ultrasound scan: if the result is positive, offer treatment; if negative, offer reassurance and consider an alternative diagnosis. 3,7

Indications for thrombophilia testing

Thrombophilia testing should be considered only in NICE-recommended clinical scenarios, as follows:3,7

  • 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
    • 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.

Investigations for cancer

Practitioners should offer all patients diagnosed with unprovoked DVT or PE, who are not already known to have cancer, the following investigations for cancer: 3,7

  • 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.

Further 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 [see 'investigations for cancer', above]. 3

Prophylaxis and treatment

The NICE pathway3 recommends appropriate mechanical (see Box 1, below) and pharmacological (see Box 2, below) interventions for VTE prophylaxis and treatment. Primary care plays a vital role in managing prophylaxis and treatment post discharge for hospitalised patients.

Box 1: Mechanical VTE prophylaxis3,4,22

  • Base the choice of mechanical VTE prophylaxis on the clinical condition of the patient, surgical procedure, and patient preference. Choose any one of:
    • anti-embolism stockings (thigh or knee length)*
    • foot impulse devices
    • intermittent pneumatic compression devices (thigh or knee length)
  • A geko device may be used in people who have a high risk of venous thromboembolism and for whom other mechanical and pharmacological methods of prophylaxis are impractical or contraindicated
  • Do not offer anti-embolism stockings to patients with:
    • suspected or proven peripheral arterial disease
    • peripheral arterial bypass grafting
    • peripheral neuropathy or other causes of sensory impairment
    • compromised local condition, such as 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
  • Staff who fit stockings should be trained in their use and should show patients how to use them
  • Use stockings that provide graduated compression and produce a calf pressure of 14–15 mmHg
  • Encourage patients to wear the stockings day and night from admission until they no longer have significantly reduced mobility
  • Remove stockings daily for hygiene purposes and to inspect skin condition.
  • * Prescribers should refer to specific product information and contraindications before offering graduated compression stockings.
  • Adapted from: NICE Pathways. Venous thromboembolism pathway. Last updated: 5 January 2015. Available at: pathways.nice.org.uk/pathways/venous-thromboembolism (accessed 22 January 2015). NICE. Venous thromboembolism: reducing the risk. Clinical Guideline 92. NICE, 2010. Available at: nice.org.uk/guidance/CG92 NICE. The geko device for reducing the risk of venous thromboembolism. Medical Technology Guidance 19. NICE, June 2014. Available at: www.nice.org.uk/guidance/MTG19
  • Reproduced with permission.

Box 2: Pharmacological interventions3,4

Low molecular weight heparin, fondaparinux, and unfractionated heparin

  • Offer a choice of 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, offer UFH with dose adjustments based on the APTT, 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
  • Consider offering synthetic alternatives (fondaparinux) to heparin (which is of animal orgin) to patients who have concerns about using animal products or with a history of heparin-induced thrombocytopenia
  • Start the LMWH, fondaparinux, or UFH as soon as possible and continue it for at least 5 days or until the INR (adjusted by a VKA) 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 6 months, assess the risks and benefits of continuing anticoagulation.

Vitamin K antagonists

  • 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.
  • 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
  • Do not offer additional pharmacological or mechanical VTE prophylaxis to patients who are taking a VKA and who are within their therapeutic range or having full anticoagulant therapy (for example, fondaparinux, LMWH or UFH), providing anticoagulant therapy is continued.

Rivaroxaban

  • Rivaroxaban is recommended by NICE, within its marketing authorisation, as an option for:
    • treating DVT and preventing recurrent DVT and PE after a diagnosis of acute DVT in adults
    • treating PE and preventing recurrent DVT and PE after a diagnosis of acute DVT in adults.

Dabigatran

Dabigatran is recommended by NICE, within its marketing authorisation, as an option for treating and for preventing recurrent DVT and PE in adults.

  • * At the time this part of the pathway was created (June 2012) some types of LMWH did 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.
  • Although this use is common in UK clinical practice, at the time this part of the pathway was created (June 2012) none of the anticoagulants had 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.
  • LMWH=low molecular weight heparin; DVT=deep vein thrombosis; PE=pulmonary embolism; UFH=unfractionated heparin; APTT= activated partial thromboplastin time; INR=international normalised ratio; VKA=vitamin K antagonist
  • Adapted from: NICE Pathways. Venous thromboembolism pathway. Last updated: 5 January 2015. Available at: pathways.nice.org.uk/pathways/venous-thromboembolism (accessed 22 January 2015).
  • NICE. Venous thromboembolism: reducing the risk. Clinical Guideline 92. NICE, 2010. Available at: nice.org.uk/guidance/CG92 (accessed 22 January 2015)
  • Reproduced with permission.

Recent developments

Novel oral anticoagulants such as dabigatran, rivaroxaban, and apixaban have been licensed and have been approved by NICE for several indications. 12,13,14,15,16,17,18,19,20 These agents provide an alternative to vitamin K antagonists. They differ from one another in their mode of action, pharmacokinetics, dosages, and licensed indications, for example, dabigatran is a direct antithrombin agent, while rivaroxaban and apixaban are direct Xa inhibitors.21 A detailed discussion on these agents is outside the scope of this article.

NICE has also recently approved a percutaneous neuromuscular electrostimulation device called a geko device, which is applied over the fibular head and works by peroneal muscle stimulation in the lower leg and foot, mimicking normal walking without the person having to move. The venous return estimated in healthy subjects was more than by traditional electromechanical devices. The geko device may be used in people who have a high risk of VTE and for whom other mechanical and pharmacological methods of prophylaxis are impractical or contraindicated.22

Patient information

NICE recommends that patients are offered verbal and written information about their condition (see Box 3, below).3,4

Box 3: Information for patients3,4,7

Before starting VTE prophylaxis/treatment, offer patients verbal and written information on:

  • risks and possible consequences of VTE
  • importance of VTE prophylaxis and its possible side-effects
  • correct use of VTE prophylaxis, (e.g. anti-embolism stockings, foot impulse or intermittent pneumatic compression devices)
  • how to reduce risk of VTE
  • how to use anticoagulants
  • duration of anticoagulation treatment
  • the effects of other medications, foods, and alcohol on oral anticoagulation treatment
  • self-monitoring of 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
  • possible side-effects of anticoagulant treatment and what to do if these occur
  • an 'anticoagulation information booklet' and an 'anticoagulation alert card' and advise patients to carry the 'anticoagulant alert card' at all times
  • Secondary care practitioners should make sure that the patient's GP is notified for seamless transfer of care.
  • VTE=venous thromboembolism
  • Adapted from: NICE Pathways. Venous thromboembolism pathway. Last updated: 5 January 2015. Available at: pathways.nice.org.uk/pathways/venous-thromboembolism (accessed 22 January 2015). NICE. Venous thromboembolism: reducing the risk. Clinical Guideline 92. NICE, 2010. Available at: nice.org.uk/guidance/CG92
  • NICE. Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. Clinical Guideline 144. NICE, 2012. Available at: nice.org.uk/guidance/cg144
  • Reproduced with permission.

Challenges to primary care

Some of the main challenges to primary care diagnosis, management, and education/training/leadership are summarised below:

Challenges in diagnosis

  • Clinical recognition of DVT/PE using the two-level Wells scoring system 8,9
  • Access to D-dimer testing
  • False positive results from D-dimer tests
  • Access to urgent radiology (proximal venous ultrasound scan, CTPA, V/Q SPECT or planar scans)
  • Implementing NICE guidance on thrombophilia testing7 to achieve efficiency savings.

Challenges in management

  • Managing non-complicated patients with VTE (i.e. without haemodynamic instability) in primary care to reduce secondary care, urgent care centre, and A&E referrals
  • Clinician awareness of, and patient compliance in, the use of mechanical prophylaxis (e.g. anti-embolism stockings) for up to 2 years to reduce the risk of PTS
  • Continuation of anticoagulants post discharge from secondary care for seamless continuity of care
  • Improving time in therapeutic international normalised ratio (INR) range (time in therapeutic range [TTR]) above the current average of 60% for patients on vitamin K antagonists, such as warfarin.17
  • Funding for NICE-approved NOAC agents
  • Education and training for practitioners regarding the use of NOAC agents
  • Optimising the uptake of NICEapproved NOAC agents with a review of funding arrangements for anticoagulation clinics.

Education, training, and leadership challenges

  • Increasing the use of web-based tools for VTE (such as e-learning packages 23) that are available on NICE and Department of Health websites
  • Patient education about primary and secondary prevention
  • Identifying local VTE champions to lead on addressing these challenges.

Many of these challenges originate at commissioning level, so efficient leadership is of paramount importance.

Improved awareness in healthcare delivery system in England

NICE and the Department of Health have issued extensive guidance over the past decade in the form of clinical guidelines, technology appraisals, quality standards, medical technology appraisals, and a VTE pathway (the most recent, current guidance is listed under 'sources' in the pathway).3 Also over the past decade, NOACs (e.g. dabigatran, rivaroxaban, apixaban) have been introduced and approved by NICE for several VTE-related indications. 12,13,14,15,16,17,18,19,20 The game-changer in terms of policy awareness for VTE prevention was the introduction of mandatory VTE assessment and prophylaxis for hospitalised patients as a CQUIN (Commissioning for Quality and Innovation) payment goal in 2011.24 In the author's opinion, the current level of VTE prevention awareness across primary and secondary care can be attributed to these various policy measures and the introduction of NOAC agents, which have provided an alternative to vitamin K antagonists.

Conclusion

The NICE VTE pathway3 provides a blueprint for primary and secondary care to reduce VTE-associated mortality and morbidity of chronic ill health and disability due to PTS. The challenge for the healthcare system is to implement the recommendations through physician and patient education, local leadership in the form of a VTE champion, and effective commissioning arrangements for diagnostics.

GPs should:

    • be competent in the clinical recognition of:
      • DVT/PE using the two-level Well's scoring system
      • NICE-approved indications for thrombophilia testing
    • have urgent access to:
      • radiology tests within 4 hours, or within 24 hours if urgent testing is not available
      • D-dimer tests
      • a referral pathway for thrombophilia tests in approved settings cancer detection tests for unprovoked DVT/PE patients
    • ensure that:
      • mechanical and pharmaceutical prophylaxis is offered for the appropriate duration in keeping with NICE recommendations
      • patients wear anti-thrombotic stockings post DVT for up to 2 years to reduce the risk of PTS

Key points

  • aim to deliver seamless continuity of care after patients with DVT/PE have been discharged from secondary care
  • receive education and training in the prescribing and use of NOAC agents
  • aim to improve TTR for patients on vitamin K antagonists
  • make use of web-based tools (such as e-learning packages) for VTE available on NICE and Department of Health websites.
  • Make sure patient information leaflets about the management of VTE are available in practices
  • aim to manage uncomplicated, haemodynamically stable VTE in primary care.

DVT=deep vein thrombosis; PE=pulmonary embolism; PTS=post thrombotic syndrome;

NOAC=novel oral anticoagulant; TTR= time in therapeutic range; VTE=venous thromboembolism

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GP commissioning messages

written by Dr David Jenner, NHS Alliance GMS contract/PBC Lead

  • NICE CG144 and NICE VTE pathway lay out clear care pathways for the diagnosis and management of VTE, with standards for timeliness of investigations, especially ultrasound scans:
    • clinical commissioning groups (CCGs) should ensure that such diagnostics are available within the NICE timeframes—this is a particular challenge at weekends and bank holidays
  • Since the publication of NICE CG144, several NOAC agents have become available and subject to NICE guidance or technology appraisal guidance:
    • CCG medicines optimisation teams should consider the role of these NOAC agents in the management of DVT; they may indeed offer cost and quality advantages over vitamin K antagonists for short-term use in DVT and should be available as an option for treatment
  • Education programmes around NICE VTE pathway for primary care clinicians, including out-of-hours GPs and walk-in centre staff, will aid effective implementation of the pathway:
    • locally appointed VTE champions may help facilitate this
  • Simple prompt cards for the Wells score tests could be produced for clinicians to carry with them on home visits, or be built into apps for smartphones to ensure that clinicians always have access to them.

VTE=venous thromboembolism; NOAC=novel oral anticoagulant; DVT=deep vein thrombosis

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References

  1. House of Commons Health Committee.The prevention of venous thromboembolism in hospitalised patients: second report of session 2004–2005. London: Stationery Office, 2005. Available at: www.publications.parliament.uk/pa/cm200405/cmselect/cmhealth/99/99.pdf
  2. Goldhaber S. Prophylaxis of venous thrombosis.Curr Treat Options Cardiovasc Med 2001; 3 (3): 225–235.
  3. NICE Pathways. Venous thromboembolism pathway. Last updated: 5 January 2015. Available at: pathways.nice.org.uk/pathways/venous-thromboembolism (accessed: 22 January 2015).
  4. NICE. Venous thromboembolism: reducing the risk. Clinical Guideline 92. NICE, 2010. Available at: nice.org.uk/guidance/CG92
  5. NICE website. Venous thromboembolism prevention quality standard. Quality Standard 3. Available at: nice.org.uk/guidance/qs3 (accessed 30 January 2015).
  6. NICE website. Quality standard for diagnosis and management of venous thromboembolic diseases. Quality Standard 29. Available at: nice.org.uk/guidance/qs29 (accessed 30 January 2015).
  7. NICE. Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. Clinical Guideline 144. NICE, 2012. Available at: nice.org.uk/guidance/cg144
  8. Wells P, Anderson D, Rodger M et al. Evaluation of D-dimer in the diagnosis of suspected deepvein thrombosis. N Engl J Med 2003; 349 (13): 1227–1235.
  9. Wells P, Anderson D, Rodger M et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer.Thromb Haemost 2000; 83 (3): 416–420.
  10. NICE website. CG144 Venous thromboembolic diseases: two-level Wells score—templates for deep vein thrombosis and pulmonary embolism. https://www.nice.org.uk/guidance/cg144/resources/cg144-venous-thromboembolic-diseases-twolevel-wells-score-templates-for-deep-vein-thrombosis-and-pulmonary-embolism- (accessed 30 January 2014).
  11. Brotman D, Segal J, Jani J et al. Limitations of D-dimer testing in unselected inpatients with suspected venous thromboembolism. Am J Med 2003; 114 (4): 276–282.
  12. NICE. Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. Technology Appraisal 157. NICE, 2008. Available at: www.nice.org.uk/guidance/ta157
  13. NICE. Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults. Technology Appraisal 170. NICE, 2009. Available at: www.nice.org.uk/guidance/TA170
  14. NICE. Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults. Technology Appraisal 245. NICE, January 2012. Available at: www.nice.org.uk/guidance/TA245
  15. NICE. Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation. Technology Appraisal 249. NICE, March 2012. Available at: www.nice.org.uk/guidance/ta249
  16. NICE. Rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation. Technology Appraisal 256. NICE, May 2012. Available at: www.nice.org.uk/guidance/TA256
  17. NICE. Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism. Technology Appraisal 261. NICE, July 2012. Available at:www.nice.org.uk/guidance/TA261
  18. NICE. Apixaban for preventing stroke and systemic embolism in people with nonvalvular atrial fibrillation. Technology Appraisal 275. NICE, February 2013. Available at: www.nice.org.uk/guidance/TA275
  19. NICE. Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thrombo-embolism. Technology Appraisal 287. NICE, June 2013. Available at: www.nice.org.uk/guidance/TA287
  20. NICE. Dabigatran etexilate for the treatment and secondary prevention of deep vein thrombosis and/ or pulmonary embolism. Technology Appraisal 327. NICE, December 2014. Available at: www.nice.org.uk/guidance/TA327
  21. Electronic Medicines Compendium. www.medicines.org.uk/emc/
  22. NICE. The geko device for reducing the risk of venous thromboembolism. Medical Technology Guidance 19. NICE, June 2014. Available at:www.nice.org.uk/guidance/MTG19
  23. NICE website. NICE care—preventing venous thromboembolism. Embolism and thrombosis. Shared learning database. January 2012. Available at: www.nice.org.uk/savings AndProductivity AndLocalPracticeResource?ci=http%3a%2f%2fsearch.nice.org.uk%2fsl_527 (accessed 22 January 2015).
  24. NHS Institute for Innovation and Improvement website. Commissioning for Quality and Innovation (CQUIN) payment framework. www.institute.nhs.uk/commissioning/pct_portal/cquin.html (accessed 29 January 2015.)