The Management of Crohn's Disease in Adults and Young People

Submitted by J. F. Mayberry, A. Lobo, A. C. Ford, A. Thomas

Tags: abdominal pain adults best practice children Chron's clinical Crohn's disease disease treatment treatment options Young People

The Management of Crohn's Disease in Adults and Young People

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Disclosures
Aliment Pharmacol
Ther. 2013;37(2):195-203.Correspondence to Prof. J. F. Mayberry, Department of Digestive Diseases, University Hospitals of Leicester NHS Trust, Leicester, LE1 5WW, UK.

Abstract and Introduction

Abstract

Background The guideline offers best practice advice on the care of adults, children and young people with Crohn's disease.

Aim To provide clinically effective and cost-effective evidence-based recommendations to guide clinical practice in a clinical guideline commissioned by the National Institute for Health and Clinical Excellence (NICE).

Methods A systematic review of the evidence including critical appraisal, meta-analysis and cost-effectiveness modelling.

Results Thirty-one evidence-based recommendations covering induction and maintenance therapy are available. Five key priorities for implementation are identified together with nine future research recommendations. Three guideline versions are available: short (containing just the recommendations), full (containing the full evidence base) and an Understanding NICE guidance for patients and carers. Algorithms have been produced together with a NICE pathway and implementation tools.

Conclusion These are the first evidence-based clinical and cost-effectiveness guidelines for Crohn's disease in the United Kingdom.

Introduction

Crohn's disease is a chronic inflammatory disease that mainly affects the gastrointestinal tract. The prevalence of Crohn's disease in the north of England was 145/100 000[1] and Scotland 157/100 000,[2] meaning there are at least 115 000 people in the UK with Crohn's disease at the present time. Up to one-third of people with Crohn's disease are diagnosed before the age of 21,[3] but there is a lack of studies on treatment for children and young people. The Guideline Development Group was particularly sensitive to issues surrounding growth and physical development as well as psychological and emotional development and educational needs. Several studies have shown a high incidence of psychological morbidity in children and young people as well as adults with Crohn's disease.[4, 5]Crohn's disease can affect the entire gastrointestinal tract, including the mouth and perianal region. The terminal ileum and colon are the most commonly affected sites. Crohn's disease runs a long-term course that includes periods of clinical remission as well as intercurrent exacerbations. People with Crohn's disease may present with symptoms that include abdominal pain, diarrhoea, weight loss and the course of the disease can be associated with considerable debility.

The approach to management therefore needs to combine appropriate deployment of medical, surgical and/or endoscopic treatment with timely information and support. The aims include improving or completely resolving symptoms, improving or restoring quality of life, avoiding hospitalisation and promoting endoscopic mucosal healing whilst minimising adverse events – particularly from drugs such as systemic glucocorticosteroids.

The National Clinical Guideline Centre (NCGC) was commissioned by the National Institute for Health and Clinical Excellence (NICE), based upon a remit received from the Department of Health, to produce a guideline for the management of Crohn's disease. A multidisciplinary Guideline Development Group (GDG) comprising professional members and consumer representatives of the main stakeholders developed the guideline. The guideline was based upon a scope,[6] which underwent consultation with stakeholders. The aim of this article is to provide a summary of the recently published evidence-based guideline, highlighting important recommendations and key changes for clinical practice.

Methods

The review questions were based upon the commissioned scope. Systematic literature searches were undertaken to identify evidence within published literature to answer the review questions in accordance with the NICE Guidelines Manual.[7] Where possible, up-to-date meta-analyses were conducted to combine the results of studies for each review question and in the case of induction of remission, network meta-analyses[8, 9] were conducted. For most intervention evidence reviews in this guideline, Cochrane systematic reviews and randomised controlled trials (RCTs) were included, as the most robust study design. The evidence for outcomes from the included RCT and observational studies was evaluated and presented using an adaptation of the 'Grading of Recommendations Assessment, Development and Evaluation (GRADE) toolbox' developed by the international GRADE working group.[10] Limitations to the evidence, inconsistency, indirectness and imprecision were taken into account for each outcome and the overall quality of evidence was considered and graded as very low, low, moderate or high.

The cost effectiveness of drug treatments was evaluated through the development of original decision models for induction of remission and maintenance of remission based upon the results of the systematic review of the clinical literature. Published cost-effectiveness evidence was graded according to applicability and methodological limitations.[7]

Recommendations and the Underpinning Evidence Base

The guidelines are based on the best available research evidence, with the aim of improving the quality of Crohn's disease care and treatment, and providing good value to the National Health Service. Predetermined and systematic methods were used to identify and evaluate the evidence relating to specific review questions. When literature searches identified little or no evidence, the Guideline Development Group based their recommendations on consensus experience of good practice. The evidence base underpinning the recommendations is provided following each recommendation. All recommendations apply to adults, children and young people, unless stated otherwise.

Recommendations

Patient Information and Support

Ensure that information and advice about Crohn's disease:

• is age appropriate

• is of the appropriate cognitive and literacy level, and

• meets the cultural and linguistic needs of the local community.

[Evidence base – Guideline Development Group (GDG) experience] 

Discuss treatment options and monitoring with the person with Crohn's disease, and/or their parent or carer if appropriate, and within the multidisciplinary team. Apply the principles outlined in 'Patient experience in adult NHS services' (NICE clinical guideline 138).[11] 

[Evidence base – GDG experience and other NICE guidance] 

Discuss the possible nature, frequency and severity of side effects of drug treatmenta with people with Crohn's disease, and/or their parents or carers if appropriate.

[Evidence base – GDG experience] 

Give all people with Crohn's disease, and/or their parents or carers if appropriate, information, advice and support in line with published NICE guidance on:

• smoking cessation

• patient experience

• medicines adherence

• fertility

[Evidence base – GDG experience and other NICE guidance] 

Give people with Crohn's disease, and/or their parents or carers if appropriate, additional information on the following when appropriate:

• possible delay of growth and puberty in children and young people

• diet and nutrition

• fertility and sexual relationships

• prognosis

• side effects of their treatment

• cancer risk

• surgery

• care of young people in transition between paediatric and adult services

• contact details for support groups.

[Evidence base – low-quality qualitative evidence] 

Offer adults, children and young people, and/or their parents or carers, age-appropriate multidisciplinary support to deal with any concerns about the disease and its treatment, including concerns about body image, living with a chronic illness and attending school and higher education.

[Evidence base – low-quality qualitative evidence]

Inducing Remission in Crohn's Disease

Monotherapy.

Offer monotherapy with a conventional glucocorticosteroid (prednisolone, methylprednisolone or intravenous hydrocortisone) to induce remission in people with a first presentation or a single inflammatory exacerbation of Crohn's disease in a 12-month period.

[Evidence base – low-, moderate-, high-quality evidence from randomised controlled trials and original cost-effectiveness model] 

Consider enteral nutrition as an alternative to a conventional glucocorticosteroid to induce remission for:

• children in whom there is concern about growth or side effects, and

• young people in whom there is concern about growth.

[Evidence base – very low- and low-quality evidence from randomised controlled trials] 

In people with one or more of distal ileal, ileocaecal or right-sided colonic diseaseb who decline, cannot tolerate or in whom a conventional glucocorticosteroid is contraindicated, consider budesonidec for a first presentation or a single inflammatory exacerbation in a 12-month period. Explain that budesonide is less effective than a conventional glucocorticosteroid, but may have fewer side effects.

[Evidence base – low-quality evidence from randomised controlled trials and original cost-effectiveness model] 

In people who decline, cannot tolerate or in whom glucocorticosteroid treatment is contraindicated, consider 5-aminosalicylate (5-ASA) treatmentd for a first presentation or a single inflammatory exacerbation in a 12-month period. Explain that 5-ASA is less effective than a conventional glucocorticosteroid or budesonide, but may have fewer side effects than a conventional glucocorticosteroid.

[Evidence base – very low-, low-, moderate-, high-quality evidence from randomised controlled trials] 

Do not offer budesonide or 5-ASA treatment for severe presentations or exacerbations.

[Evidence base – very low- and low-quality evidence from randomised controlled trials] 

Do not offer azathioprine, mercaptopurine or methotrexate as monotherapy to induce remission.

[Evidence base – very low- and moderate-quality evidence from randomised controlled trials]

Additional Therapy.

Consider adding azathioprine or mercaptopurinee to a conventional glucocorticosteroid or budesonide to induce remission of Crohn's disease if:

• there are two or more inflammatory exacerbations in a 12-month period, or

• the glucocorticosteroid dose cannot be tapered.

[Evidence base – very low-, low- and moderate-quality evidence from randomised controlled trials and original cost-effectiveness model] 

Assess thiopurine methyltransferase (TPMT) activity before offering azathioprine or mercaptopurine.f Do not offer azathioprine or mercaptopurine if TPMT activity is deficient (very low or absent). Consider azathioprine or mercaptopurine at a lower dose if TPMT activity is below normal, but not deficient (according to local laboratory reference values).

[Evidence base – low-quality evidence from randomised controlled trials and a published cost-effectiveness model (which was partially applicable with potentially serious limitations)] 

Consider adding methotrexate[e,f] to a conventional glucocorticosteroid or budesonide to induce remission in people who cannot tolerate azathioprine or mercaptopurine, or in whom TPMT activity is deficient if:

• there are two or more inflammatory exacerbations in a 12-month period, or

• the glucocorticosteroid dose cannot be tapered.

[Evidence base – very low-quality evidence from randomised controlled trials and original cost-effectiveness model] 

Monitor the effects of azathioprine, mercaptopurine and methotrexatef,g as advised in the current online version of the 'British national formulary' (BNF) or 'British national formulary for children' (BNFC). Monitor for neutropaenia in those taking azathioprine or mercaptopurine even if they have normal TPMT activity.

[Evidence base – GDG experience and BNF/BNFC] 

Ensure that there are documented local safety monitoring policies and procedures (including audit) for adults, children and young people receiving treatment that needs monitoring. Nominate a member of staff to act on abnormal results and communicate with GPs and people with Crohn's disease and/or their parents or carers, if appropriate.

[Evidence base – GDG experience]

The GDG cross-referred to TA187 Crohn's disease - infliximab and adalimumab: guidance:[12] Infliximab and adalimumab, within their licensed indications, are recommended as treatment options for adults with severe active Crohn's disease whose disease has not responded to conventional therapy (including immunosuppressive and/or corticosteroid treatments), or who are intolerant of or have contraindications to conventional therapy. Infliximab or adalimumab should be given as a planned course of treatment until treatment failure (including the need for surgery), or until 12 months after the start of treatment, whichever is shorter. People should then have their disease reassessed to determine whether ongoing treatment is still clinically appropriate.

All recommendations from TA187 pertaining to infliximab and adalimumab for the treatment of Crohn__s disease can be found at http://guidance.nice.org.uk/TA187/Guidance/pdf/English.

Maintaining Remission in Crohn's Disease

Discuss with people with Crohn's disease, and/or their parents or carers if appropriate, options for managing their disease when they are in remission, including both no treatment and treatment. The discussion should include the risk of inflammatory exacerbations (with and without drug treatment) and the potential side effects of drug treatment. Record the person's views in their notes.

[Evidence base – GDG experience]

Follow-up During Remission for Those Who Choose not to Receive Maintenance Treatment.

When people choose not to receive maintenance treatment:

• discuss and agree with them, and/or their parents or carers if appropriate, plans for follow-up, including the frequency of follow-up and who they should see

• ensure they know which symptoms may suggest a relapse and should prompt a consultation with their healthcare professional (most frequently, unintended weight loss, abdominal pain, diarrhoea, or general ill-health)

• ensure they know how to access the healthcare system if they experience a relapse

• discuss the importance of not smoking.

[Evidence base – GDG experience]

Maintaining Remission.

Offer azathioprine or mercaptopurinee as monotherapy to maintain remission when previously used with a conventional glucocorticosteroid or budesonide to induce remission.

[Evidence base – low- and moderate-quality evidence from randomised controlled trials and original cost-effectiveness model] 

Consider azathioprine or mercaptopurinee to maintain remission in people who have not previously received these drugs (particularly those with adverse prognostic factors such as early age of onset, perianal disease, glucocorticosteroid use at presentation and severe presentations).

[Evidence base – low- and moderate-quality evidence from randomised controlled trials and original cost-effectiveness model] 

Consider methotrexatee,f to maintain remission only in people who:

• needed methotrexate to induce remission, or

• have tried, but did not tolerate azathioprine or mercaptopurine for maintenance or

• have contraindications to azathioprine or mercaptopurine (for example, deficient TPMT activity or previous episodes of pancreatitis).

[Evidence base – low-quality evidence from randomised controlled trials] 

Do not offer a conventional glucocorticosteroid or budesonide to maintain remission.

[Evidence base – low- and moderate-quality evidence from randomised controlled trials and original cost-effectiveness model]

Maintaining Remission After Surgery

Consider azathioprine or mercaptopurinee to maintain remission after surgery in people with adverse prognostic factors such as:

• more than one resection, or

• previously complicated or debilitating disease (for example, abscess, involvement of adjacent structures, fistulising or penetrating disease).

[Evidence base – very low-quality evidence from randomised controlled trials and a published cost-effectiveness model (which has partial applicable, but only minor methodological limitations)] 

Consider 5-ASA treatmentd to maintain remission after surgery.

[Evidence base – very low-, low- and moderate-quality evidence from randomised controlled trials] 

Do not offer budesonide or enteral nutrition to maintain remission after surgery.

[Evidence base – very low- and low-quality evidence from randomised controlled trials]

Surgery

Crohn's Disease Limited to the Distal Ileum.

Consider surgery as an alternative to medical treatment early in the course of the disease for people whose disease is limited to the distal ileum, taking into account the following:

• benefits and risks of medical treatment and surgery

• risk of recurrence after surgery

• individual preferences and any personal or cultural considerations

• record the person's views in their notes.

[Evidence base – GDG experience] 

Consider surgery early in the course of the disease or before, or early on in, puberty for children and young people whose disease is limited to the distal ileum and who have:

• growth impairment despite optimal medical treatment and/or

• refractory disease.

[Evidence base – very low-quality evidence from observational studies] 

Discuss treatment options within the multidisciplinary team and with the person's parent or carer and, if appropriate, the child or young person.

[Evidence base – GDG experience]

Managing Strictures.

Consider balloon dilation particularly in people with a single stricture that is short, straight and accessible by colonoscopy.

[Evidence base – very low-quality evidence from observational studies] 

Discuss the benefits and risks of balloon dilation and surgical interventions for managing stricturesiwith:

• the person with Crohn's disease and/or their parent or carer if appropriate and

• a surgeon and

• a gastroenterologist.

[Evidence base – GDG experience] 

Take into account the following factors when assessing options for managing a stricture:

• whether medical treatment has been optimised

• the number and extent of previous resections

• the rapidity of past recurrence (if appropriate)

• the potential for further resections

• the consequence of short bowel syndrome

• the person's preference, and how their lifestyle and cultural background might affect management.

[Evidence base – GDG experience] 

Ensure that abdominal surgery is available for managing complications or failure of balloon dilation.

[Evidence base – GDG experience]

Monitoring for Osteopaenia and Assessing Fracture Risk

The GDG referred to the NICE clinical guideline on 'Osteoporosis: assessing the risk of fragility fracture' (NICE clinical guideline 146) for recommendations on assessing the risk of fragility fracture in adults.[13] Crohn's disease is a cause of secondary osteoporosis.

Do not routinely monitor for changes in bone mineral density in children and young people.

[Evidence base – very low-quality evidence from observational studies] 

Consider monitoring for changes in bone mineral density in children and young people with risk factors, such as low body mass index (BMI), low trauma fracture or continued or repeated glucocorticosteroid use.

[Evidence base – GDG experience]

Conception and Pregnancy

Give information about the possible effects of Crohn's disease on pregnancy, including the potential risks and benefits of medical treatment and the possible effects of Crohn's disease on fertility.

[Evidence base – GDG experience] 

Ensure effective communication and information-sharing across specialties (for example, primary care, obstetrics and gastroenterology) in the care of pregnant women with Crohn's disease.

[Evidence base – GDG experience]

Discussion of the Current Controversies

The NICE guideline is an evidence-based guideline in which the available evidence is assessed using a rigorous, transparent, written process that includes clinical and cost-effectiveness analyses. The full guideline is available at http://guidance.nice.org.uk/CG152/Guidance.

Given the extent of the processes and methodology applied, and the need to ensure speedy delivery of up-to-date evidence-based guidance, the commissioned scope was limited to priority areas, confirmed by stakeholders. The guideline, therefore, did not set out to be a fully comprehensive guide to all aspects of Crohn's disease.

Although there are clear strengths from the robustness of the process, there are some limitations. Some areas are excluded from the scope of this guideline – although are clearly important. The diagnosis of Crohn's disease, diagnostic tests and diagnostic criteria were not addressed. The use of anti-TNF agents is addressed in existing Technology Appraisal (TA) 187, and this has been incorporated into the guideline – update work was outside of the remit of the commissioned scope. Endoscopic therapy is only part of the overall treatment strategy for people with strictures complicating Crohn's disease.

There was a paucity of high-quality data, with many published studies under-powered and lacking homogeneity. Given the chronic and periodic nature of the disease, longer term studies would have been helpful, but few were available. The diverse anatomical sites affected make it difficult to conduct randomised controlled studies in which both the intervention and placebo arm contain comparable patient populations. An extensive literature search revealed no other network meta-analyses in the field. For the first time in Crohn's disease, network meta-analysis (NMA)[8, 9] was used to try to give a more complete picture for drug interventions. A limitation of this approach is that it requires that trials of A vs. B, B vs. C, A vs. C, etc. are all similar in terms of their population, treatment protocols, outcome measures, etc. This was mitigated by analysing separately trials of first-line treatment and those in patients who had failed to reach remission with a glucocorticosteroid. Reassuringly, when the NMA results were compared with the direct meta-analysis results,9 significant inconsistency between the results of different trial comparisons was not found.

It is increasingly acknowledged that the choice of outcomes in trials of interventions in Crohn's disease is of the greatest importance – to ensure that outcomes of relevance to patients and clinicians are captured, including those that may lead to an improved long-term course, such as healing of the intestinal mucosa. To avoid data dredging, outcomes were agreed a priori. Few studies reported mucosal healing. In addition, outcome measures need to reflect not only statistical significance but also benefits, which are of clinical significance and are considered valuable by patients. In line with published NICE processes, two patient and carer members with extensive experience of the disease contributed fully to the guideline and helped to shape the recommendations, which may differ from other guidelines.

Particularly given the paucity of evidence in children, the group extrapolated and generalised from adult populations to children when there were no or little data for specific populations. In practice, the GDG agreed to base treatment recommendations on RCTs with extrapolation to childhood if no separate paediatric evidence was found.

Clinicians are rightly cautious of the use of systemically bioavailable glucocorticosteroids, because of short- and long-term side effects. First-line induction therapy with a glucocorticosteroid has been recommended here because of the direct evidence of benefit compared with other treatments – including controlled ileal-release budesonide – and no treatment. Controlled ileal-release budesonide may be used when distal ileal, ileocaecal or right-sided colonic area/s are affected, and when there are concerns about adverse events associated with conventional glucocorticosteroid treatment. Although budesonide demonstrated fewer side effects, the withdrawal rates were similar to prednisolone. The health economic decision model showed that a treatment strategy starting with conventional glucocorticosteroid treatment was the most cost-effective treatment for an inflammatory exacerbation of Crohn's disease. Modelling explored the effects of including drug-related adverse events. The analysis showed that when the additional risks of myocardial infarction and hip fracture associated with glucocorticosteroid monotherapy were accounted for in the model and the likely additional costs and reduction in quality of life quantified, the most cost-effective strategy did not change. Details regarding the model can be found in the Appendix H of the full guideline.[14] To allow for concerns about inappropriate repeat glucocorticosteroid prescribing, the group limited the recommendation to 'a first presentation or single exacerbation in a 12-month period' and highlighted the need to consider those who may be at higher risk of running a debilitating course.

Economic analysis is an important component of NICE methodology, but the analysis clearly depends on the strength of the data informing the models, and the assumptions made. For Crohn's disease, outlining the typical course of disease was particularly challenging, as the site and severity of presenting symptoms and its treatment vary greatly between individuals and data are limited. Furthermore, the comparative incidence of specific adverse events for different drugs and their treatment outcome was extremely difficult to quantify. It is hoped that future research will improve this, but in the meantime, these analyses were subjected to extensive sensitivity analyses and recommendations were made with caution where necessary.

In addition, other issues of particular note include:

  • There were few RCTs of azathioprine or mercaptopurine or methotrexate for induction of remission, maintenance of remission, or preventing relapse of disease activity after surgery. With regard to azathioprine/mercaptopurine after ileal resection, the GDG was aware that a large UK study is in progress.

  • The 5-ASA trials for maintenance of remission did not report efficacy according to disease location, which may have been helpful to tease out whether they are effective in isolated colonic vs. isolated small bowel disease.

  • There were no RCTs, at the time of writing, that compare surgery with medical therapy for isolated distal ileal disease.

  • The evidence for enteral nutrition was particularly limited. There were no placebo controlled RCTs and the glucocorticosteroid controlled RCTs were of low- or very low-quality. More are needed in children.

It is the combination of a robust clinical evidence review using criteria defined a priori and techniques such as network meta-analysis, with economic evidence review, which gives substance to these guidelines – and which may lead to recommendations that diverge from those based on interpretation of the data and expert opinion. Nevertheless, these techniques can never fully compensate for limitations in the original literature. Important areas of continuing uncertainty have been identified in recommendations for further research. It is important that clinicians involved in the management of people with Crohn's disease take on the challenge of developing and conducting studies to address these within the changing landscape of available treatments.

References

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  2. Steed H, Walsh S, Reynolds N. Crohn's disease incidence in NHS Tayside. Scott Med J 2010; 55: 22–5.

  3. Gomez J. Living with Crohn's Disease (Overcoming Common Problems). London: Sheldon Press, 2000.

  4. Engstrom I. Mental health and psychological functioning in children and adolescents with inflammatory bowel disease: a comparison with children having other chronic illnesses and with healthy children. J Child Psychol Psychiatry 1992; 33: 563–82.

  5. Guthrie E, Jackson J, Shaffer J, Thompson D, Tomenson B, Creed F. Psychological disorder and severity of inflammatory bowel disease predict health-related quality of life in ulcerative colitis and Crohn's disease. Am J Gastroenterol 2002; 97: 1994–9.

  6. National Clinical Guideline Centre. The Management of Crohn's Disease. Appendix A: Scope [October 19, 2012]. London: Royal College of Physicians, 2012. Available at: http://guidance.nice.org.uk/CG152/Guidance/Appendices/pdf/English. Accessed October 19, 2012.

  7. National Institute for Health and Clinical Excellence. The Guidelines Manual. London: National Institute for Health and Clinical Excellence, 2009. Available at: http://www.nice.org.uk/boutnice/howwework/developingniceclinicalguidelines/

    clinicalguidelinedevelopmentmethods/GuidelinesManual2009.jsp. Accessed October 19, 2012.

  8. Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ 2005; 331: 897–900.

  9. Dias S, Welton NJ, Sutton AJ, Ades AE. NICE DSU Technical Support Document 2: a generalised linear modelling framework for pairwise and network meta-analysis of randomised controlled trials. 2011. Available at: http://www.nicedsu.org.uk. Accessed October 19, 2012.

  10. GRADE Working Group. The grading of recommendations assessment, development and evaluation (GRADE) working group website. 2011. Available at: http://www.gradeworkinggroup.org. Accessed October 19, 2012.

  11. National Clinical Guideline Centre. Patient Experience in Adult NHS Services: Improving the Experience ofCare for People Using Adult NHS Services. NICE Clinical Guideline CG138. London: Royal College of Physicians, 2012. Available at: http://guidance.nice.org.uk/CG138. Accessed October 19, 2012.

  12. National Institute for Health and Clinical Excellence. NICE Technology Appraisal Guidance 187. Infliximab(Review) and Adalimumab for theTreatment of Crohn's Disease. Includesa Review of NICE Technology AppraisalGuidance 40. 2010. Available at: http://guidance.nice.org.uk/TA187. Accessed October 19, 2012.

  13. National Clinical Guideline Centre. Osteoporosis: Assessing the Risk of Fragility Fracture. London: Royal College of Physicians, 2012. Available at: http://guidance.nice.org.uk/CG146. Accessed October 19, 2012.

  14. National Clinical Guideline Centre. The Management of Crohn's Disease. Appendix H: Full health economics report [October 2012]. London: Royal College of Physicians, 2012. Available at: http://guidance.nice.org.uk/CG152/Guidance/Appendices/pdf/English. Accessed October 19, 2012.