1. © IPCRG 2007 Achieving asthma control in practice: understanding the reasons for poor control September 2008

2. Page 2 - © IPCRG 2007 International panel discussion, Aberdeen, Sept 2007 How to develop tools for use in primary care: o To identify causes of poor asthma control o To manage causes of poor asthma control We're not treating asthma; we're treating patients. Many of our patients would not be eligible for inclusion in randomised controlled trials because of comorbidities and other factors. Thus, the asthma guidelines, which are based on results of these trials, often do not provide the answers we need for patient care, particularly in the primary care setting. -Dr. John Haughney Haughney J et al. Achieving asthma control in practice: understanding the reasons for poor control. Respir Med. 2008;102:1681–93.

3. Page 3 - © IPCRG 2007 What is asthma control? As defined by the Global Initiative for Asthma (GINA), 2007 Minimal to no daytime asthma symptoms No limitations on activities No nocturnal symptoms or awakenings Minimal to no need for reliever or rescue therapy Normal lung function (FEV 1 or PEF) No exacerbations www.ginasthma.org

4. Page 4 - © IPCRG 2007 Reasons for poor asthma control Wrong diagnosis or confounding illness Incorrect choice of inhaler or poor technique Concurrent smoking Concomitant rhinitis Unintentional or intentional nonadherence Individual variation in treatment response Undertreatment Haughney J et al. Respir Med. 2008;102:1681–93.

5. Page 5 - © IPCRG 2007 Addressing poor asthma control Step 1: Confirm the diagnosis of asthma If the patient is not responding as expected to asthma therapy: oConfirm the asthma diagnosis and rule out (or in) confounding illness before changing or increasing medications Tools for diagnosing asthma must be stratified by age Objective measures of reversible airflow obstruction (spirometry, PEF) are important if available IPCRG Guidelines: diagnosis of respiratory diseases in primary care. Prim Care Respir J. 2006;15:20–34.

6. Page 6 - © IPCRG 2007 Diagnosing asthma in primary care IPCRG guidelines. Prim Care Respir J. 2006;15:20–34. Compatible clinical history oEpisodic or persistent dyspnoea, wheeze, tightness, cough oTriggers (allergic, irritant) oRisk factors for asthma development oConsider occupational asthma for adults with recent onset Objective evidence oSpirometry or peak expiratory flow oBronchoprovocation test (methacholine challenge) Ancillary tests oChest x-ray oEosinophils, IgE level oAllergy testing oExhaled nitric oxide oInduced sputum

7. Page 7 - © IPCRG 2007 Diagnosing asthma in children Remember that young children commonly wheeze with colds Differentials for wheezing include respiratory (upper and lower) and non-respiratory causes: oUpper airway: allergic diseases oObstruction of large airway: foreign body, vocal cord dysfunction, vascular rings, laryngeal webs, tracheomalacia, or stenosis oObstruction of small airways: viral bronchiolitis, cystic fibrosis, bronchopulmonary dysplasia, heart disease oOther: aspiration (gastro-oesophageal reflux disease) Spirometry is usually impractical for patients < 5 years old Bush A. Diagnosis of asthma in children under five. Prim Care Respir J. 2007;16:7–15.

8. Page 8 - © IPCRG 2007 Modified Asthma Prediction Index (mAPI) A clinical index defining asthma risk in 2–3 year olds One of three major risk factors: 1.Parental history of asthma 2.Physician-diagnosed atopic dermatitis 3.Allergic sensitization to ≥1 aeroallergen OR two of three minor risk factors: 1.Allergic sensitization to milk, egg, or peanuts 2.Wheezing unrelated to colds 3.Blood eosinophils ≥4% For a child ≥2 years old with a history of ≥4 wheezing episodes (≥1 confirmed by a physician), the likelihood of active asthma at age 6-13 yrs increases if the child has: Guilbert TW et al. J Allergy Clin Immunol. 2004;114:1282–7.

9. Page 9 - © IPCRG 2007 Diagnosing asthma in adults Differentiate between asthma and chronic obstructive pulmonary disease (COPD) Identify triggers such as smoking, pet exposure, occupational exposure Common differential diagnoses: oCOPD, cardiac disease, laryngeal, tracheal, or lung tumour, bronchiectasis, foreign body, interstitial lung disease, pulmonary emboli, aspiration, vocal cord dysfunction, hyperventilation IPCRG Guidelines: diagnosis of respiratory diseases in primary care. Prim Care Respir J. 2006;15:20–34.

10. Page 10 - © IPCRG 2007 Diagnosing asthma in adults Comorbidities can worsen asthma symptoms— identify and treat them: allergic rhinitis COPD gastro-oesophageal reflux disease (GERD) respiratory infection cardiac disorders anaemia vocal cord dysfunction

11. Page 11 - © IPCRG 2007 Addressing poor asthma control Incorrect inhaler choice or poor technique There is no clinical difference between inhaler devices when used correctly, but each type requires a different pattern of inhalation for optimal drug delivery to the lungs Problems with inhaler technique are common in clinical practice & can lead to poor asthma control Asthma control worsens as the number of mistakes in inhaler technique increases All patients should be trained in technique, and trainers should be competent with the inhalation technique

12. Page 12 - © IPCRG 2007 Inhaler choice and technique Key recommendations: Take patient preference into account when choosing the inhaler device Simplify the regimen and do not mix inhaler device types The choice of steroid inhaler is most important because of the narrower therapeutic window Invest the time to train each patient in proper inhaler technique: Observe technique & let patient observe self (using video demonstrations) Devices to check technique & maintain trained technique are available (eg, 2Tone Trainer & Aerochamber Plus spacer for metered dose inhalers; In- Check Dial, Turbuhaler whistle, Novolizer for dry powder inhalers) Recheck inhaler technique on each revisit Haughney J et al. Respir Med. 2008;102:1681–93.

13. Page 13 - © IPCRG 2007 Resources on inhaler use Inhaler & spacer diagrams on GINA website: ohttp://www.ginasthma.com/Userfiles/inhaler_charts.pdfhttp://www.ginasthma.com/Userfiles/inhaler_charts.pdf American College of Chest Physicians/American College of Asthma, Allergy, and Immunology guidelines: o Dolovich et al. Chest. 2005;127:335-371. Educational CD-Roms by Ontario Thoracic Society Provider Education Program: ohttp://www.on.lung.ca/Health-Care-Professionals/Provider- Education-Program/CD-ROMS.phphttp://www.on.lung.ca/Health-Care-Professionals/Provider- Education-Program/CD-ROMS.php Schematic cartoons on the Asthma UK website: ohttp://www.asthma.org.uk/using_your.htmlhttp://www.asthma.org.uk/using_your.html

14. Page 14 - © IPCRG 2007 Resources on inhaler use (cont.) Correct Inhaler Techniques and Common Mistakes oJune 2008 newsletter, National Asthma Council, Australia: http://www.nationalasthma.org.au/html/newsletter/2008/nl_08_006.asp#s2 http://www.nationalasthma.org.au/html/newsletter/2008/nl_08_006.asp#s2 oWoolcock Institute of Medical Research: http://www.woolcock.org.au/PDF/PR/WIMR_Press_Release_AsthmaMeds_Ju ne2008.pdf http://www.woolcock.org.au/PDF/PR/WIMR_Press_Release_AsthmaMeds_Ju ne2008.pdf Asthma Management Handbook 2006, National Asthma Council, Australia: oUse & care of spacers: http://www.nationalasthma.org.au/cms/index.php?option=com_content&task=vi ew&id=200&Itemid=147 http://www.nationalasthma.org.au/cms/index.php?option=com_content&task=vi ew&id=200&Itemid=147 oDelivery devices: http://www.nationalasthma.org.au/cms/index.php?option=com_content&task=vi ew&id=90&Itemid=112 http://www.nationalasthma.org.au/cms/index.php?option=com_content&task=vi ew&id=90&Itemid=112

15. Page 15 - © IPCRG 2007 Addressing poor asthma control Concurrent smoking Smoking adversely impacts asthma control oCurrent smokers are almost 3 times more likely than non-smokers to be hospitalised for their asthma over a 12-month period Why does smoking adversely impact asthma? oAsthma misdiagnosed as COPD or concomitant COPD oRelative steroid resistance Price D et al. Clin Exp Allergy. 2005;35:282–7.

16. Page 16 - © IPCRG 2007 Inhaled steroids are less effective in smokers than nonsmokers with asthma The pattern of airway inflammation differs Smokers have a higher percentage of neutrophils in induced sputum, and steroids are not very effective in reducing neutrophils. Smoking produces oxidative stress The oxidative stress produced by smoking impairs the activity of histone deacetylase-2 (HDAC2), resulting in reduced anti-inflammatory activity of steroids. Smoking triggers leukotriene production Leukotrienes are not reduced by steroid therapy. Boulet LP et al. Chest. 2006;129:661–8. Barnes PJ et al. Lancet. 2004;363:731–3. Fauler J et al. Eur J Clin Invest. 1997;27:43–7.

17. Page 17 - © IPCRG 2007  GM-CSF  IL-8  eotaxin Histoneacetylation Inflammatory stimuli Non-Smoking Asthma NF-  B GR  HDAC2  Histone acetylation Corticosteroids Steroidresponse Steroid resistance in smokers with asthma Cigarette smoke Oxidative stress Histoneacetylation Peroxynitrite Smoking Asthma  HDAC2 NF-  B  GM-CSF  IL-8  eotaxin Steroidresistance GM-CSFIL-8eotaxin GR = glucocorticoid receptors; HDAC2 = histone deacetylase-2; NF-  B = nuclear factor-  B

18. Page 18 - © IPCRG 2007 Clinical approach to smoking Tools oTake a smoking history oInvestigate the possibility of COPD IPCRG guidance includes tool to differentiate asthma from COPD* Solutions oEncourage smokers to quit! IPCRG guidance on smoking cessation: http://www.theipcrg.org/smoking/index.php http://www.theipcrg.org/smoking/index.php oTry alternative therapy: Leukotriene receptor antagonist Possibly theophylline *IPCRG Guidelines: diagnosis of respiratory diseases in primary care. Prim Care Respir J. 2006;15:20–34.

19. Page 19 - © IPCRG 2007 Addressing poor asthma control Concomitant rhinitis Patients with asthma & concomitant rhinitis use more health care resources than those without rhinitis In epidemiologic studies in the UK: oAdults with asthma & concomitant rhinitis were 50% more likely to be hospitalised for their asthma & significantly more likely to visit their primary care physician than those without rhinitis oChildren with asthma & concomitant rhinitis had double the likelihood of being hospitalised and significantly increased likelihood of a physician visit for asthma than those without rhinitis >50% of patients with asthma have rhinitis oBoth allergic & nonallergic rhinitis are linked to asthma Price D et al Clin Exp Allergy. 2005;35:282–7. Thomas M et al. Pediatrics. 2005;115:129–34.

20. Page 20 - © IPCRG 2007 Evidence linking asthma & rhinitis >50% of patients with asthma have rhinitis Similar epidemiology Common triggers Similar pattern of inflammation: oT helper type 2 cells, mast cells, eosinophils Nasal challenge results in asthmatic inflammation & vice versa Rhinitis predicts development of asthma Thomas M. BMC Pulm Med. 2006;6:S4.

21. Page 21 - © IPCRG 2007 Does treatment of rhinitis improve asthma control? Preliminary evidence suggests that it does improve asthma control In the COMPACT trial, patients with comorbid rhinitis who received budesonide plus montelukast, a leukotriene receptor antagonist effective in treating rhinitis symptoms in patients with asthma, showed significantly greater improvement in morning PEF than the group receiving monotherapy with doubled dose of budesonide. This treatment difference was not seen among patients without comorbid rhinitis, suggesting that the effects of montelukast on rhinitis improved lung function. Price DB et al. Allergy. 2006;61:737–42.

22. Page 22 - © IPCRG 2007 Clinical approach to rhinitis Diagnosing rhinitis oUse the International Study of Asthma and Allergies in Childhood (ISAAC) question: "Do you have an itchy, sneezy, runny, or blocked nose when you don't have a cold?“ oTake a good history & examine the nose oAssess severity – as relates to asthma control Treat the inflammation of both asthma & rhinitis oTarget upper & lower airways concomitantly or oCombine upper plus lower airway therapies IPCRG Guidelines: management of allergic rhinitis. Prim Care Respir J. 2006;15:58–70.

23. Page 23 - © IPCRG 2007 Treatment of comorbid rhinitis & asthma Upper airway treatment optionsLower airway treatment options Nasal steroidsInhaled steroids Antihistamines Upper and lower airway treatment options Leukotriene receptor antagonists Anti-IgE Immunotherapy

24. Page 24 - © IPCRG 2007 Addressing poor asthma control Unintentional & intentional nonadherence Nonadherence to asthma therapy, particularly to inhaled steroids, is a common problem contributing to poor asthma control Nonadherence is often a hidden problem as assessment of adherence is often not included in routine asthma review Barriers to assessing adherence: oPatient and physician may prefer to avoid the subject oLack of clear, easy methods for addressing barriers to adherence oPerception that little can be done? Appreciating the factors involved is the first step toward improving adherence Horne R. Chest. 2006;130:65S–72S.

25. Page 25 - © IPCRG 2007 Unintentional versus intentional nonadherence Horne R et al. 2005. National Co-ordinating Centre for NHS Service Delivery and Organisation R&D, London. Intentional nonadherence derives from the balance between the patient’s beliefs about the personal necessity of taking a given medication relative to any concerns about taking it

26. Page 26 - © IPCRG 2007 Nonadherence: identifying the causes Tools for identifying & assessing nonadherence: oBeliefs about Medicines Questionnaire (BMQ) — developed to measure necessity beliefs and concerns oMedication Adherence Report Scale (MARS) — developed to assess patient adherence oMinimal Asthma Assessment Tool (MAAT) — undergoing pilot testing as a simple, self- administered patient questionnaire for use before a clinical consultation to evaluate asthma control, adherence to medication, and comorbidities such as allergic rhinitis and smoking Interventions to facilitate optimal adherence are likely to be more effective if they: oFacilitate honest discussion of adherence behaviour oIdentify the mix of perceptual & practical barriers for the individual patient oHelp clinicians to elicit and respond to patient beliefs and concerns We need to tailor the intervention & support according to specific barriers & patient preferences Haughney J et al. Respir Med. 2008;102:1681–93.

27. Page 27 - © IPCRG 2007 Addressing poor asthma control Individual variation in treatment response 1.Fewer than 10% of people with asthma in a general practice population are eligible for the typical RCT 2.Patient adherence to therapy may be better in an RCT than in the real world 3.The definition of “response” to therapy in an RCT (eg, FEV 1 improvement) may not correspond to results relevant for our patients (eg, improved asthma control, improved quality of life) 4.The inclusion/exclusion criteria can influence RCT results (eg, requirement for bronchodilator reversibility may favour β agonist) 5.Group mean data from RCTs may not predict individual patient response Randomised controlled trials (RCTs) are the basis of recommendations made by clinical guidelines. However, several factors limit our ability to generalise RCT results to our patients. Haughney J et al. Respir Med. 2008;102:1681–93.

28. Page 28 - © IPCRG 2007 Individual variation in treatment response Distribution of FEV 1 responses among adults with chronic asthma after 12 weeks of therapy with inhaled beclometasone (white bars) or oral montelukast (striped bars). The mean FEV 1 improvement from baseline was 13.1% for beclometasone & 7.4% for montelukast. Malmstrom K et al. Ann Intern Med. 1999;130:487–95.

29. Page 29 - © IPCRG 2007 Individual variation in treatment response Individual patient versus average patient Intraindividual response profile to therapy among children and adolescents with persistent asthma. Individual patient responses (change from baseline in asthma control days) suggest that, while some patients responded to both inhaled steroid and montelukast, others showed a better response to one or the other. Zeiger RS et al. J Allergy Clin Immunol. 2006;117:45–52.

30. Page 30 - © IPCRG 2007 Difficulty in capturing & demonstrating subjective benefit in clinical trials Factors driving clinical trials: Regulatory requirements The needs of industry History owhat's been done in the past & is therefore still expected Ease of measuring certain endpoints Available technology to measure these endpoints The need to focus on short-term events of asthma The limited number of agents available for treating asthma The need to remove all possible confounding factors to allow assessment of the intervention studied Haughney J et al. Respir Med. 2008;102:1681–93.

31. Page 31 - © IPCRG 2007 Real world measures are needed for clinical trials Haughney J et al. Respir Med. 2008;102:1681–93.

32. Page 32 - © IPCRG 2007 Addressing poor asthma control Next steps— IPCRG GOALS Develop tools to aid asthma diagnosis and management in primary care Translate tools into local languages and adapt them to address cultural differences in perceptions about asthma Test all tools to address issue of low levels of health literacy in many countries Coordinate efforts between the IPCRG, member countries, and patients’ organisations to adapt tools for individual countries