Anthony D. D’Urzo MD, MSc , CCFP, FCFP Associate Professor,

1. The Safe Use of Long-Acting Beta-Adrenoceptor Agonists – LABAs: The Importance of differentiating Asthma from COPD Anthony D. D’Urzo MD, MSc, CCFP, FCFP Associate Professor, Department of Family and Community Medicine University of Toronto Chair, Primary Care Respiratory Alliance of Canada (PCRC) Director, Primary Care Lung Clinic, Toronto www.lungclinic.ca

2. The Safe Use of Long-Acting Beta-Adrenoceptor Agonists – LABAs: The Importance of differentiating asthma from COPD ReuvenJhirad MD, CCFP, FCFP Lecturer, Department of Family and Community Medicine University of Toronto Member , Primary Care Respiratory Alliance of Canada (PCRC)

3. Disclosure Anthony D. D’Urzo : Have received speaker fees and research grants from several pharmaceutical organizations to participate in educational events and research activities involving the role of LABAs in asthma and COPD management.

4. Disclosure Revven Jhirad : none declared

5. The Safe Use of Long-Acting Beta-Adrenoceptor Agonists – LABAs: The Importance of differentiating Asthma from COPD Acknowledegments Dr ItamarTamari * (DFCM, U of T) Dr Pieter Jugovic * (DFCM, U of T) Dr Jacques Bouchard* (University of Montreal) * Members: Primary Care Respiratory Alliance of Canada (PCRC)

6. The Safe Use of Long-Acting Beta-Adrenoceptor Agonists – LABAs: The Importance of differentiating Asthma from COPD Objectives • Historical perspective on beta-agonist safety • review safety concerns around LABA use in asthma management • discuss the role of LABAs in the management of chronic obstructive pulmonary disease (COPD) • discuss the importance of differentiating asthma from COPD and the risk of disease misclassification

7. The Safe Use of Long-Acting Beta-Adrenoceptor Agonists – LABAs: The Importance of differentiating Asthma from COPD Historical Perspective • Spitzer W.O et al. N Engl J Med 1992; 326: 501-6 • use of beta-agonists (especially fenoterol) administered by MDI* associated with increased risk of death from asthma (O.R. 2.6 per canister /month) • Castle et al. BMJ 1993; 306 (6884): 1034-7 • Numerical increase (3 fold) in asthma deaths with salmeterol use compared to salbutamol. • UK General Practitioners (25,180 patients) * metered dose inhaler

8. The Safe Use of Long-Acting Beta-Adrenoceptor Agonists – LABAs: The Importance of differentiating Asthma from COPD Historical Perspective • D’Urzo AD et al. Chest 2001; 119 (3): 714-9 Effectiveness and safety of salmeterol in Nonspecialist practice settings • Salmeterol treatment is effective in asthmatic subjects typically cared for in the primary care setting and does not increase the frequency of severe exacerbations.

9. The Safe Use of Long-Acting Beta-Adrenoceptor Agonists – LABAs: The Importance of differentiating Asthma from COPD • Pauwels RA et al. N Engl J Med. 1997; 337 (20): 1405-11 Formoterol And Corticosteroids Establishing Therapy (FACET) • addition of formoterol to budesonide therapy improves symptoms (exacerbations) and lung function compared to budesonide alone.

10. The Safe Use of Long-Acting Beta-Adrenoceptor Agonists – LABAs: The Importance of differentiating Asthma from COPD • O’Byrne PM et al. Am J Respir Crit Care Med 2001; 164(8): 1392-1397 Low dose Inhaled budesonide and formoterol in mild persistent asthma • In corticosteroid – free patients, low dose inhaled budesonide alone reduced severe exacerbations and improved asthma control • In patients already receiving inhaled corticosteroids, adding formoterol was more effective than doubling the corticosteroid dose

11. The Safe Use of Long-Acting Beta-Adrenoceptor Agonists – LABAs: The Importance of differentiating Asthma from COPD • Bateman ED et al. Am J RespirCrit Care Med 2004; 170 (8): 836-44 Can Guideline defined asthma control be achieved? The Gaining Optimal Asthma Control Study. • asthma control achieved more rapidly and at a lower corticosteroid dose with salmeterol / fluticasonevsfluticasone • Exacerbation rates and health status were significantly better with salmeterol / fluticasone.

12. The Safe Use of Long-Acting Beta-Adrenoceptor Agonists – LABAs: The Importance of differentiating Asthma from COPD A Controversy Emerges • Nelson HS et al. Chest 2006; 129 (1): 15-26 The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol (SMART) • drug manufacturer asked by the FDA to conduct a post marketing surveillance study which began in 1996.

13. Nelson HS et al. Chest 2006; 129 (1): 15-26

14. The Safe Use of Long-Acting Beta-Adrenoceptor Agonists – LABAs: The Importance of differentiating Asthma from COPD A Controversy Emerges • Salpter ER et al. Ann Intern Med 2006; 144 (12): 904 -12 Meta-analysis: effect of long-acting B2-agonists on severe asthma exacerbations and asthma related deaths • conclusions based primarily on the results of SMART trial, Nelson HS et al. Chest 2006; 129 (1): 15-26

15. The Safe Use of Long-Acting Beta-Adrenoceptor Agonists – LABAs: The Importance of differentiating Asthma from COPD The Food and Drug Administration addresses the Controversy around LABA safety in Asthma Management 2008* • Expert panel warns against continued use of salmeterol and formoterol as monotherapy for adults and children with asthma *www.fda.gov/ohrms/dockets/ac/08/transcripts/2008.4398+2-day2.pdf. Accessed 2009 Dec 16

16. The Safe Use of Long-Acting Beta-Adrenoceptor Agonists – LABAs: The Importance of differentiating Asthma from COPD • Jaeschke R. et al. Am J Respir Crit Care Med 2008; 178:1009-1016 The Safety of Long-Acting B-agonists (LABA) among patients with asthma using Inhaled Corticosteroids: Systemic Review and Meta- analysis. • in the patients using inhaled corticosteroids, LABA use did not increase the risk of asthma related hospitalizations.

17. The Safe Use of Long-Acting Beta-Adrenoceptor Agonists – LABAs: The Importance of differentiating Asthma from COPD Current Perspective Safety of long-acting B2-agonists (LABA) in the management of asthma: A Primary Care Respiratory Alliance of Canada (PCRC) Perspective Can Fam Physician 2010; 56: 119-20 • LABAs should be added if symptoms are not adequately controlled on low-to-moderate dose of inhaled corticosteroids.

18. The Safe Use of Long-Acting Beta-Adrenoceptor Agonists – LABAs: The Importance of differentiating Asthma from COPD FDA Drug Safety Communication: New safety requirements for long-acting inhaled asthma medications called Long-acting Beta-Agonists (LABAs). Safety Announcement (02-18-2010) • The use of LABAs is contraindicated without the use of an asthma controller medication such as an inhaled corticosteroid. Single-ingredient LABAs should only be used in combination with an asthma controller medication; they should not be used alone • LABAs should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controller medications • LABAs should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved. Patients should then be maintained on an asthma controller medication • Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA, to ensure compliance with both medications

19. The Safe Use of Long-Acting Beta-Adrenoceptor Agonists – LABAs: The Importance of differentiating Asthma from COPD Current Perspective Canadian Thoracic Society Asthma Committee commentary on long-acting beta-2-agonist use for asthma in Canada Lougheed MD, et al. Can Respir J 2010; 17(2): 57-8 • Concur with FDA but caution that the FDA recommendation that “LABA be used for the shortest duration possible to achieve control of asthma symptoms and then discontinued” is not evidence based.

20. Differentiating Asthma from COPD • Why is this important?

21. Differentiating Asthma from COPD • First Line Therapy • Asthma - Inhaled glucocorticosteroids • COPD - Inhaled bronchodilator therapy – long acting for maintenance: ↓ hyperinflation ↑ inspiratory capacity IMPORTANT • Long-acting-β2-agonist monotherapy contraindicated in ASTHMA

22. Differentiating Asthma from COPD

23. Role of Spirometry in COPD DiagnosisCOPD Diagnosis Confirmed by Spirometry “Airflow Obstruction” Consistent reduction in the ratio of FEV1/FVC < 0.70 or LLN* * LLN = lower limit of normal FEV1 = Forced expiratory volume in one second FVC = Forced vital capacity O’Donnell DE et al. CTS Recommendations for Management of COPD. 2008 Update Highlights for Primary Care. Can Resp J 2008; 15(SupplA): 1A-8A

24. Role of Spirometry in Asthma Diagnosis Increased FEV1 by 12 % or 200 cc after B2-agonist challenge* FEV1/FVC not formerly included in diagnostic decision making *CMAJ 1999; 161: 51-61.

25. FEV1: Maximal volume of air exhaled after a maximal inhalation in the first second of a forced exhalationFVC: Maximal volume of air exhaled after inhalation during a forced exhalation* FVC < 80 predicted = full pulmonary function tests (PFTs) to rule out hyperinflation vs. combined obstructive and restrictive defect** FVC > 80% predicted***FEV1 and FVC < 80% predicted****The % change is calculated as Postbronchodilator FEV1 – Prebronchodilator FEV1 divided by the Prebronchodilator FEV1. FEV1 may not improve after β2-agonist challenge.*****Lack of change in FEV1 is non-diagnostic; referral for Methacholine challenge recommended. Can Fam Physician, in press

26. Can Fam Physician, in press

27. Summary/Conclusion • LABAs should not be used as monotherapy in asthma • In asthma patients who remain symptomatic on regular ICS medication, addition of LABA therapy may improve asthma control • LABAs can be used as monotherapy in patients with COPD • Using historical and spirometric data may facilitate differention of asthma from COPD and minimize inappropriate therapeutic intervention